AU2008281509A1 - Pyrimidine and pyridine derivatives and their pharmaceutical use and compositions - Google Patents

Pyrimidine and pyridine derivatives and their pharmaceutical use and compositions Download PDF

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AU2008281509A1
AU2008281509A1 AU2008281509A AU2008281509A AU2008281509A1 AU 2008281509 A1 AU2008281509 A1 AU 2008281509A1 AU 2008281509 A AU2008281509 A AU 2008281509A AU 2008281509 A AU2008281509 A AU 2008281509A AU 2008281509 A1 AU2008281509 A1 AU 2008281509A1
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methyl
pentyl
propyl
butyl
substituted
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AU2008281509A
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Jeffery Neal Carroll
Theresa R. Fletcher
Margaret L. Grapperhaus
Bruce Cameron Hamper
Cathleen Elizabeth Hanau
Mark Alan Massa
Joseph J. Mcdonald
Matthew David Mcreynolds
Mark Anthony Morris
Joe Nahra
Patrick Michael O'brien
William Howard Roark
Michael David Rogers
Peter G. Ruminski
Michelle Ann Schmidt
Mark E. Schnute
Jeffrey Allen Scholten
Joseph Walter Strohback
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Pfizer Inc
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Pfizer Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Description

WO 2009/016498 PCT/IB2008/002046 Pyrimidine and Pyridine Derivatives and Their Pharmaceutical Use and Compositions Field of the Invention This invention relates to pyrimidine and pyridine derivatives. Such compounds have been shown to inhibit matrix metalloproteinase enzymes. These compounds are useful for treating diseases 5 resulting from MMP-mediated tissue breakdown such as heart disease, cardiac insufficiency, inflammatory bowel disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, fibrotic disorders in the kidney, lung, and/or osteoporosis. 10 Background of the Invention Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs, or an imbalance between MMPs and inhibitors of MMPs, have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues. 15 To date, 24 different members of the MMP family have been identified in vertebrates, 23 of which are found in human, including collagenases (MMP-1, MMP-8, MMP-1 3), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, MMP-11), matrilysins (MMP-7 and MMP-26), membrane-type (MMT-14, MMP-15, MMP-16, MMT-17, MMP-24, MMT-25), as well as metalloelastases (MMP-12, MMP-19, MMP-20, MMP-22, MMP-23) (See Visse and Nagase (2003) 20 Circ. Res. 92:827-839) These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. Inhibiting matrix metalloproteinase enzymes, thereby curtailing and/or eliminating 25 the breakdown of connective tissues that results in the disease states, is a recognized method for preventing and treating these and other diseases. There is a catalytic zinc domain in matrix metalloproteinases that is typically the focal point for inhibitor design. The modification of substrates by introducing zinc-chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates 30 and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases; see, e.g., US. Patent No. 5,948,780. A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular enzyme. Recent data has established that specific MMP enzymes are associated with 35 some diseases, with no effect on others. The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue. This is evidenced by the recent discovery that MMP-1 3 alone is over 1 WO 2009/016498 PCT/IB2008/002046 expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Amer. Chem. Soc., 2000;122:9648-54). Selective inhibitors of MMP-1 3 include a compound named WAY 170523, which has been reported by Chen et al., supra, 2000. Other selective inhibitors of MMP-13 are reported in International 5 Patent Application Publication No. WO 05/105760. Other selective inhibitors of MMP-13 are reported in U.S. Patent Application Publication No. US20030229103. Other selective inhibitors of MMP-13 are reported in U.S. Patent Application Publication No. US20040167120. Other selective inhibitors of MMP-13 are reported in U.S. Patent Application Publication No. US200500041 11. Other selective inhibitors of MMP-13 are reported in U.S. Patent Application Publication No. US20060173183. Other 10 selective inhibitors of MMP-13 are reported in International Patent Application Publication No. WO 06/128184. Other selective inhibitors of MMP-13 are reported in Co-assigned International Patent Application Publication No. WO 02/64572. Other selective inhibitors of MMP-13 are reported in Co assigned International Patent Application Publication No. WO 02/64599. U.S. Patent No. 6,008,243 discloses inhibitors of MMP-13. However, no selective or nonselective inhibitor of MMP-13 has been 15 approved and marketed for the treatment of any disease in any mammal. Accordingly, the need continues to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for use clinically in the prevention and treatment of the associated disease states. Summary of the Invention 20 The present invention provides compounds of Formula 1: 0 WN L G H I M Q Y wherein G is (C 1
.
3 alkylenyl)-Ra or Ra, wherein said C1.3 alkylenyl may be substituted by one or more substituents selected from OH and F; 25 Ra is C1- alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C1- alkyl may be substituted by one or more substituents selected from F, -OR3, -SR3, -C(=O)NR'R 35 , -NRR 35 , -NR 3 4 C(=O)R 3 , or -NR3SO 2
R
3 6 , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R 2 , R 3 , R4, R5, R *, R", and R2; 30 M is N or C-Rb; Q is N or C-Rc, provided that if Q is C-Rc, M is N; W is phenyl-(C- 6 alkylenyl), pyridyl-(C-e alkylenyl), or 9-membered heteroaryl-(C- 6 alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R and R3; 35 Y is C 1
-
6 alkyl, C 1
-
6 haloalkyl; or C 1
-
6 hydroxyalkyl; 2 WO 2009/016498 PCT/IB2008/002046 L is 5-membered heteroaryl;
R
2 is H, F, CN, -OR 5 , R' 2 , -C(=O)R', -NR 8 R 3 , -NR"C(=O)R, -NR'S0 2
R
36 , or -S0 2
R
1 2 ; R3 is H, F, CN, or -OR2;
R
4 is H, -(C 1
.
6 alkylene)Rr, -C(=O)R 9 , or -SO 2
R
12 ; 5 R is H or -(CIe alkyl), wherein said C 1 .. alkyl may be substituted by one or more R substituents;
R
6 is H, CN, -OR 23 , -S0 2
R
37 , -NR 24 C(0)R 23 , -NR 24
SO
2
R
37 , or N-N R is -(C1. alkyl), -(C 1 e haloalkyl), -(C 1 e alkylene)OH, -NRaR 3, -NHSO 2
CH
3 , or -OR ; R9 is -(C1.6 alkylene)FR", -NHR 24, or -OR ; 10 R10 is H, F, CN, R , or -C(=0)R'; R" is H, F, CN, -OR 5 , R 2 , -C(=O)R', -NR 8
R
33 -NR'C(=0)R 9 , -NR'SO 2
R'
6 , or -S0 2
R'
2 ;
R
1 2 is -(C1.6 alkyl), wherein said C1.6 alkyl may be substituted by one or more substituents selected from CN, -OR , -SRZ , -SO 2 R 3, -NR R , -NR 24
C(=O)R
23 , and -NR 24SO 2 R , provided that any one carbon atom of said C1. alkyl is not substituted by more than one CN or more than 23, 15 one -OR ; Rb, Rc, R8, R 20 , R 22 , FR 24 , R 25 , R 3 3,
R
34 , and R 3 5 are independently H or -(C16 alkyl); R is H, F, orR 12; R 2 is H, -(C1_ alkyl), or -(C1.6 alkylene)OH; R26 is H, OH, halo, NH2, or SH; 20 R 28 is H, NH2, or -OR 29 ; R is H, (Cie alkyl), or -C(=0)(CI- 6 alkyl);
R
3 0 is H or F; R 1 is F, Cl, Br, -CN, -C(=0)NH 2 , -OH, -OR , -OCH 2
CH
2 OR , R2, ,or (C1_ alkyl) optionally substituted by -OR 2 5 or -OCH 2
CH
2 0R 25 25 where R34 and R' when adjacent may be taken together to constitute a group of the formula O-(CH 2 )n- or -O-(CH2)n-O-; n is 1 or 2;
R
32 is -(Cte alkyl) optionally substituted with one, two, or three F;
R
3 6 is -(Coe alkyl) or -(C3.6 cycloalkyl); and 30 R 37 is -(C1.6 alkyl), -(C3.6 cycloalkyl), or -(C1e alkylene)OH;
R
38 and R 39 are independently H, -(C6 alkyl), or R 3 8 and R 39 taken together form a 5- or 6 membered heterocycloalkyl; or a pharmaceutically-acceptable salt thereof. This invention also includes pharmaceutically acceptable salts, solvates and hydrates of 35 compounds of Formula 1. This invention also includes all tautomers and stereochemical isomers of these compounds. This invention also is directed, in part, to a method for treating an MMP-13 mediated disorder in a mammal. Such disorders include rheumatoid arthritis and osteoarthritis. The method comprises 3 WO 2009/016498 PCT/IB2008/002046 administering a compound of Formula I or a pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically-effective to treat the condition. Detailed Description of the Invention One embodiment of the invention is a compound of Formula I as shown above. 5 Another embodiment of the invention is a compound of Formula I wherein Ra is C1.6 alkyl, 1,4 dioxanyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidinyl, cyclopentyl, 7-oxa-bicyclo[2.2.1]heptanyl, piperazinyl, 1,1'-dioxothiomorpholinyl, tetrahydro-1,1'-dioxothiopyranyl, tetrahydrothiopyranyl, piperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or oxazolidinonyl, wherein said alkyl may be substituted by one or more substituents selected 10 from -OR3, -SR3, -C(=O)NR3R 3 ', -NR 34
R
35 , -NR3C(=O)R 3 , or -NR3SO 2
R
35 , and wherein said 1,4 dioxyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidiny), cyclopentyl, 7-oxa-bicyclo[2.2.1]heptanyl, piperazinyl, 1,1'-dioxothiomorpholinyl, tetrahydro-1,1'-dioxothiopyranyl, tetrahydrothiopyranyl, piperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or oxazolidinonyl may be substituted by one or more substituents selected from R 2 , R 3 , R 4 , R 5 , Rio, R", 15 and R". Another embodiment of the invention is a compound of Formula I wherein R' is Cj.6 alkyl, 1,4 dioxanyl substituted by R 1 0 and R , piperidinyl substituted by R 2 and R 3 or by R 4 , cyclohexyl substituted by R 2 and R 3 or by R 4 , morpholinyl substituted by R 4 , thiomorpholinyl substituted by R'* 21 311 21 and R , tetrahydropyranyl substituted by R 3 and R" or by Rio and R , tetrahydropyranonyl, 20 pyrrolidinyl substituted by R 2 and R 3 or by R 4 , cyclopentyl substituted by R 2 and R 3 , 7-oxa bicyclo[2.2.lheptanyl, piperazinyl substituted by R 4 and R 5 , 1,1'-dioxothiomorpholinyl, tetrahydro-1,1' dioxothiopyranyl, tetrahydrothiopyranyl, piperidinonyl substituted by R 5 , tetrahydrofuryl substituted by
R
3 and R", pyrrolidinonyl substituted by R 5 , oxazolidinonyl substituted by R , wherein said alkyl may be substituted by one or more substituents selected 25 from -OR3, -SR", -C(=0)NR 34
R
35 , -NR 3 4
R
35 , -NR 4 C(=O)R", or -NR 3 4 S0 2
R
3 1. Another embodiment of the invention is a compound of Formula I wherein Ra is C1.6 alkyl, O /10 2R N R4 O Ax I
R
3 N
R
3 0 Rio R 2 R 4 R xx /0 R2 0N Q AQ O Rio Ri 0
R
21
R
2
R
3
R
2
R
5 N R5 NC R/ 4 ::04 0 eR3 N-R R 0 R 4 WO 2009/016498 PCT/IB2008/002046 N-R5 N-R 5 0 , or 0 , wherein said alkyl may be substituted by one or more substituents selected from -OR 34 , -SR", -C(=O)NR"R, -NR R 3 , -NR3C(=O)R", or -NR 3
SO
2
R
3 5 ; and X is N or CH, provided that when X is N, G is (C2-3 alkylenyl)-Ra, wherein said C1.3 alkylenyl 5 may be substituted by one or more substituents selected from OH and F. Another embodiment of the invention is a compound of Formula I wherein Ra is C1.3 alkyl, xx R21 R3 R3 R3 02 R 10 R 4
R
1 R 3 o 2R wherein said alkyl may be substituted by one or more substituents selected from -OR4, -SR3, -C(=O)NR3R 5 , -NR 3 R", -NR34C(=O)R 5 , or -NR3SO 2 R . 10 Another embodiment of the invention is a compound of Formula I wherein Ra is C1.6 alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR 3 4 , -SR3, -C(=O)NR 34
R
35 , -NR 3 4
R
35 , -NR 34
C(=O)R
35 , or -NR3SO 2
R
3 1. Another embodiment of the invention is a compound of Formula I wherein Ra is C1.6 alkyl, 34 wherein said alkyl may be substituted by one or more -OR 15 Another embodiment of the invention is a compound of Formula I wherein Ra is R 21 R) R3 R3Q 0 R' 0
R
4
R
11
R
2
R
3 , or
R
2 5 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula I wherein Ra is /0 0 R21 R 3
R
3
R
10 R 2
R
2 3 or
R
3 R 2 Another embodiment of the invention is a compound of Formula 11: 0 W, L ,G H N N 5 Y| wherein G is (C 1
.
3 alkylenyl)-Ra or Ra, wherein said C1.3 alkylenyl may be substituted by one or more substituents selected from OH and F; Ra is C1_ alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C1.6 alkyl may be substituted by one or more substituents selected from 10 F, -OR3, -SR 3 , -C(=O)NR34R3, -NRR 3, -NRC(=O)R 35 , or -NR3SO 2 R3, and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R 2 , R 3 , R4, R5, R', R", and R2; W is phenyl-(Cr-e alkylenyl), pyridyl-(C- 6 alkylenyl), or 9-membered heteroaryl-(Cr-e alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected 15 from R3 and R3; Y is C-6 alkyl, Cr-6 haloalkyl; or C1re hydroxyalkyl; L is 5-membered heteroaryl; R2 is H, F, CN, -OR , R , -C(=O)R', -NRR 33 , -NRaC(=O)R 9 , -NR"S0 2
R
3 5, or -SO2R1; R3 is H, F, CN, or -OR2; 20 R 4 is H, -(Coe alkylene)R 6 , -C(=0)R 9 , or -SO2R2; R is H or -(C1.6 alkyl), wherein said C1. alkyl may be substituted by one or more R2 substituents; 0
R
23 R2 is H, ON, -OR 2 , -SO 2 R , -NR 24C(=O)R 23 , -NR 24SO 2 R", or N-N R is -(C 1 e alkyl), -(C1.6 haloalkyl), -(C6 alkylene)OH, -NR 3 8
R
9 , -NHSO 2
CH
3 , or -OR2; 25 R9 is -(Cl.6 alkylene)R 2, -NHR 2, or -OR2; R" is H, F, CN, R , or -C(=O)R 7 ; R" is H, F, CN, -OR 5 , R' 2 , -C(=0)R , -NRR 3, -NR 8 C(=0)R, -NR'SO 2 R , or -SO 2 R2; 6 WO 2009/016498 PCT/IB2008/002046
R
1 2 is -(Ce alkyl), wherein said C16 alkyl may be substituted by one or more substituents selected from CN, -OR2, -SR , -SO 2 R", -NR R", -NR 24C(=)R2, and -NR 24SO 2 R , provided that any one carbon atom of said C1.6 alkyl is not substituted by more than one CN or more than one -OR2; 5 Rb, Rc, R8, R 2 0, R 22 , R 24 , R 2 ', R 33 , R 3 4 , and R 3 5 are independently H or -(C1_6 alkyl); R2 is H, F, or R2; R is H, -(C-6 alkyl), or -(C1_6 alkylene)OH; R2 is H, OH, halo, NH 2 , or SH; R is H, NH 2 , or -OR2; 10 R is H, (C1.6 alkyl), or -C(=O)(Ce alkyl);
R
30 is H or F; 31 32 25 32 R is F, CI, Br, -CN, -C(=O)NH 2 , -OH, -OR , -OCH 2
CH
2 OR , R , ,or (C1.6 alkyl) optionally substituted by -OR or -OCH 2
CH
2 OR2 where R 3 0 and R 3 1 when adjacent may be taken together to constitute a group of the formula 15 0-(CH 2 )n- or -O-(CH 2 )n-O-; n is 1 or 2; R is -(C1.6 alkyl) optionally substituted with one, two, or three F; R is -(C1.6 alkyl) or -(C3.6 cycloalkyl); and
R
37 is -(C6 alkyl), -(C3.6 cycloalkyl), or -(C.6 alkylene)OH; 20 R 38 and R 39 are independently H, -(C6 alkyl), or R 38 and R 3 9 taken together form a 5- or 6 membered heterocycloalkyl; or a pharmaceutically-acceptable salt thereof. 25 Another embodiment of the invention is a compound of Formula llA: 0 W L Ra H N N Y llA wherein R', W, Y, and L are as defined hereinabove for Formula 11. Another embodiment of the invention is a compound of Formula IIA wherein L is triazolyl, tetrazolyl, or oxadiazolyl. 30 Another embodiment of the invention is a compound of Formula llA wherein L is H N-Ns N N -N, N''N N'-O0 O'N A IN>. N N N, N or 7 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula IIA wherein L is N s N N- -' N N N-, or Another embodiment of the invention is a compound of Formula llA-I o N-N, Ra W N NN-/ H N N Y llA-1 5 wherein Ra, W, and Y are as defined hereinabove for Formula 11. Another embodiment of the invention is a compound of Formula llA-2 o N Ra N N N N Y IIA-2 wherein Ra, W, and Y are as defined hereinabove for Formula 11. Another embodiment of the invention is a compound of Formula IIA-3 o N N. Ra WN N H N N 10 Y IIA-3 wherein Ra, W, and Y are as defined hereinabove for Formula 11. Another embodiment of the invention is a compound of Formula IIA-4 0 N-O Ra o NNN Y IIA-4 wherein Ra, W, and Y are as defined hereinabove for Formula 11. 15 Another embodiment of the invention is a compound of Formula lhA, IIA-1, llA-2, IIA-3, or IIA-4 O R21R 3 wherein Ra is CI alkyl, RR 0 R4 8 WO 2009/016498 PCT/IB2008/002046
R
3
R
2 1 0 R0 R 10
R
10
R
21
R
2
R
3 R5 NN
R
3 0 R 0
N-R
5 N- R 5 R 3 N -- R4 O _ R0 O or ,wherein said alkyl may be substituted by one or more substituents selected 5 from -OR 3 4 , -SR 34 , -C(=O)NRR 34
R
3 , -NR 34
R
3 5 , -NR 3 C(=0)R 35 , or -NR1 4 S0 2
R
35 Another embodiment of the invention is a compound of Formula IIA, IIA-1, IIA-2, IIA-3, or IIA-4 R21 R 3 N R 3 wherein R' is C 1 .6 alkyl, R 10
R
2 R R
R
2
R
3 , or R 2 R, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR 34 , -C(=O)NR 34
R
35 , -NR 3 4
R
35 , -NR 34 C(=O)R 3 , or -NR1 4 S0 2 R". 10 Another embodiment of the invention is a compound of Formula llA, IIA-1, IIA-2, IIA-3, or IIA-4 wherein Ra is C 1 .e alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR 4 , -SR3, -C(=O)NR R 3 5 , -NR 34
R
35 , -NR 34 C(=0)R 3 , or -NR 3 4 S0 2
R.
35 Another embodiment of the invention is a compound of Formula llA, llA-1, IIA-2, IIA-3, or IIA-4 wherein Ra is C1.6 alkyl, wherein said alkyl may be substituted by one or more -OR3. 15 Another embodiment of the invention is a compound of Formula llA, llA-1, llA-2, IIA-3, or IIA-4 R21 R3R wherein Ra is R1 0
R
2
R
4
R
11
R
2
R
3 or R 2
R
3 9 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula IIA, IIA-1, IIA-2, IIA-3, or IlA-4 wherein Y is methyl. Another embodiment of the invention is a compound of Formula llA, llA-1, IIA-2, IIA-3, or IIA-4 wherein W is phenyl-(C-e alkylenyl), wherein said phenyl is substituted by one or more groups 5 selected from R 3 * and R . Another embodiment of the invention is a compound of Formula llA, IIA-1, IIA-2, IIA-3, or IIA-4 wherein W is phenylmethyl, wherein said phenyl is substituted by one or more groups selected from
R
3 ' and R Another embodiment of the invention is a compound shown in Table 1. Table 1 Compound Name Structure N-(4-fluoro-3-methoxybenzyl)-6-(2-((5- F (h ydrox ym eth yl)- 1, 4-dioxa n-2-yl)m ethyl)- 0 2H-tetrazol-5-yl)-2-methylpyrimidine-4-
H
3 C carboxamide O N sN N N N N N CHI 0
OH
3 OH N-(4-fluoro-3-methoxybenzyl)-6-(2- F (((2S,5R)-5-(hydroxymethyl)-1,4-dioxan- 110 2-yl)methyl)-2H-tetrazol-5-yl)-2-
H
3 C methylpyrimidine-4-carboxamide O N:N NN N N N HI0 N N 0
CH
3 OH N-(4-fluoro-3-methoxybenzyl)-6-(2- F (((2R,5S)-5-(hydroxymethyl)-1,4-dioxan- O 2-yl)methyl)-2 H-tetrazol-5-yl)-2- H3C methylpyrimidine-4-carboxamide O N eN N N N H 0~ N YN Oj CH3 HOH 10 WO 2009/016498 PCT/1B2008/002046 Table 1 Corn ound Name Structure N-(3-methoxybenzyl)-6-(2-((5-0 (hydroxymethy)-1 ,4-dioxan-2-yI)methyl)-
H
3 0" 2H-tetrazol-5-yI)-2-methylpyrimidifle-4 carboxamide O N::N.
--
/ N N N H N .,.N
OH
3 OH NW-(3 -methoxybenzyl)-6-(2-(((2S, 5R)-5 (hydroxymethyl)-1 ,4-dioxan-2-yI)methyl)- H 3 C 2 H-tetrazol-5-yI)-2-methylpyrimidine-4 carboxamicle 0 N:N\ N NN HI0 0
CH
3 OH N-(3-methoxybenzyl)-6-(2-(((2R,5S)-5-0 (hydroxymethyl)-1 ,4-dioxan-2-yI)methyl)-
H
3 C" 2H-tetrazo-5-y)-2-methylpyrimidine-4 carboxamide 0 N::N, N N 0 H
OH
3 6-(2-((1,4-dioxan-2-yl)methyl)-2H- F tetrazoi-5-yI)-N-(4-fluoro-3 methoxybenzyl )-2-methylpyrimidine-4- H 3 0" carboxamide O N N, N'Y N H0
OH
3 WO 2009/016498 PCT/1B2008/002046 Table I Compound Name Structure 6-(2-(((S)-1 ,4-dioxan-2-yl)methyt)-2H- F tetra zol- 5-yl)-N -(4-Aluoro-3 -0 methoxybenzyl )-2-methylpyrimidine-4- 11 3 C" " carboxamide O N :N\
-
NN HI0 y ~0j
OH
3 N-(3-methoxybenzyl)-6-(2-(((S)-4- H 3 'o ' acetylmorpholin-2-yl)methyl)-2H-tetrazol- H3 5-yi)-2-methyipyrimidine-4-carboxamide N N N N
CH
3 (lr,4r)-4-((5-(6-((3- -N methoxybenzyi)carbamoyl)-2- N" meth ylpyrim idin-4-yI)-2 H-tetrazol-2- -' N O H yi)methyl)cyclohexanecarboxylic acid NH -r ON (1r,4r)-4-((5-(6-((4-fluoro-3- F methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2- -N 0 1 yI)methyl)cyclohexanecarboxylic acid NH -r OH 0 1 N 0 O N N-(4-fiuoro-3-methoxybenzyl)-6-(5- F ((trans-4-acetamidocyclohexyl)methyl) 1 ,2,4-oxadiazol-3-yI)-2-methylpyrimidine- 0 N'0 4-carboxamide N ~/:II:~% NH -N 0 N H 0N 12 WO 2009/016498 PCT/IB2008/002046 Table I Compound Name Structure N-(4-fluoro-3-methoxybenzyl)-6-(1 - F (((trans)-4-acetamidocyclohexyl)methyl)- N 1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine- o N N ' 4-carboxamide O H NH - N N H 0 N Another embodiment of the invention is a compound of Formula IlIl: 0 W.L N G H Rb Y iii wherein G is (C1.3 alkylenyl)-Ra or Ra, wherein said C1.3 alkylenyl may be substituted by one or 5 more substituents selected from OH and F; Ra is C 1 .6 alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C1.6 alkyl may be substituted by one or more substituents selected from F, -OR', -SR , -C(=O)NR"R , -NR R , -NR C(=O)R 35 , or -NR'S0 2 R , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R 2 , R 3 , 10 R 4 , R , R , R", and R; W is phenyl-(C1- alkylenyl), pyridyl-(C-e alkylenyl), or 9-membered heteroaryl-(C 1
-
6 alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroary) is substituted by one or more groups selected from R 3 0 and R 3 ; Y is C,-s alkyl, C,-6 haloalkyl; or C,-6 hydroxyalkyl; 15 L is 5-membered heteroaryl; R2 is H, F, CN, -OR5, R", -C(=O)R', -NRR 3, -NR 8 C(=O)R, -NR 8
SO
2 R , or -SO 2 R1; R3 is H, F, CN, or -OR2; R4 is H, -(C1 alkylene)R 6 , -C(=O)R 9 , or -SO 2 R2; R is H or -(C1 alkyl), wherein said C_ alkyl may be substituted by one or more R2 20 substituents; 0 R 23 6 23 R' is H, CN, -OR , -SO 2
R
3 ', -NR 24
C(=O)R
23 , -NR 24 S0 2 R 3 , or N-N R is -(C,. alkyl), -(C1 haloalkyl), -(C,.6 alkylene)OH, -NRUR 39 , -NHSO 2
CH
3 , or -OR2 R is -(C1 alkylene)R 28 , -NHR 2, or -OR2s RN is H, F, CN, R , or -C(=O)R 7 ; 25 R1 is H, F, CN, -OR , R 2, -C(=O)R , -NRR 3, -NRC(=0)R', -NR'SO 2 R 3, or -SO 2 R1; 13 WO 2009/016498 PCT/IB2008/002046
R
1 2 is -(Coe alkyl), wherein said C1.6 alkyl may be substituted by one or more substituents selected from CN, -OR, -SR 2 3 , -SO 2 R", -NR 8 R3, -NR 24
C(=O)R
23 , and -NR 24 S0 2 R 2 , provided that any one carbon atom of said CIe alkyl is not substituted by more than one CN or more than one -OR 23 ; 5 Rb, Rc, R 8 , R , R2, R24, R2, R3, R34, and R are independently H or -(C 1 . alkyl); R is H, F, or R2; R is H, -(CIe alkyl), or -(Ci- alkylene)OH; R is H, OH, halo, NH 2 , or SH; R is H, NH 2 , or -OR"; 10 R 29 is H, (COI alkyl), or -C(=O)(Ce alkyl);
R
3 0 is H or F; R is F, Cl, Br, -CN, -C(=O)NH 2 , -OH, -OR 2 , -OCH 2
CH
2 0R 2, R , ,or (C'.4 alkyl) optionally substituted by -OR or -OCH 2
CH
2 0R2 where R3 and R when adjacent may be taken together to constitute a group of the formula 15 O-(CH 2 )n- or -O-(CH 2 )n-O-; n is 1 or 2; R is -(C1.6 alkyl) optionally substituted with one, two, or three F; R is -(C,.6 alkyl) or -(C3.6 cycloalkyl); and
R
37 is -(C,.6 alkyl), -(C3.6 cycloalkyl), or -(C16 alkylene)OH; 20 R and R3 are independently H, -(C6 alkyl), or R and R taken together form a 5- or 6 membered heterocycloalkyl; or a pharmaceutically-acceptable salt thereof. Another embodiment of the invention is a compound of Formula lIlA: 0 W N L . Ra HN Rb Ra b Y lIlA 25 wherein Ra, Rb, W, and Y are as defined hereinabove for Formula 111. Another embodiment of the invention is a compound of Formula IllA wherein L is triazolyl, tetrazolyl, or oxadiazolyl. Another embodiment of the invention is a compound of Formula IlIlA wherein L is H N-Ns N N -Ns N'-N N'O O'N N ,\r ,or 30 Another embodiment of the invention is a compound of Formula lilA wherein L is N-Ns NA N-Ns N'O N N NN I \ , or Another embodiment of the invention is a compound of Formula lIlA-1 14 WO 2009/016498 PCT/IB2008/002046 0 N N, Ra N N N N H I R - N Rb Y lilA-1 wherein RB, Rb, W, and Y are as defined hereinabove for Formula Ill. Another embodiment of the invention is a compound of Formula IIIA-2 o N -:~\ Ra W N Rb Y IlIlA-2 5 wherein Ra, Rb, W, and Y are as defined hereinabove for Formula Ill. Another embodiment of the invention is a compound of Formula IIIA-3 o N:N, Ra WN H Rb -N Y IIlA-3 wherein R', Rb, W, and Y are as defined hereinabove for Formula 1i1. Another embodiment of the invention is a compound of Formula IIIA-4 o N- 0 Ra W N N H R VN 10 Y IIIA-4 wherein RB, R , W, and Y are as defined hereinabove for Formula 111. Another embodiment of the invention is a compound of Formula lilA, lIlA-1, IIIA-2, IIIA-3, or R R 3 N IlA-4 wherein RB is C 16 alkyl, R 10
R
2
R
4 ,R
R
3
R
21 0 R0 , R' 0
R
10
R
21
R
2
R
3 15 WO 2009/016498 PCT/IB2008/002046 R5 NN
R
3 0 O R2 , R 4 0 0// R3 N-R4
N-R
5
N-R
5 R O , or 0 ,wherein said alkyl may be substituted by one or more substituents selected from -OR 34 , -SR2, -C(=O)NR'R", -NR"R", -NR C(=0)R", or -NR3S0 2
R
35 . 5 Another embodiment of the invention is a compound of Formula lIlA, lilA-1, IIIA-2, IIIA-3, or O R21 R3 IA-4 wherein Ra is C.6 alkyl, 0 0
R
2 ,4 /0 A,/
R
3 R , R2 R3 ,or R2 , wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR34R 3 , -NR R 35 , -NR 34 C(=0)R, or -NR SO 2 R. 10 Another embodiment of the invention is a compound of Formula lIlA, lIlA-1, IIIA-2, IIIA-3, or IIIA-4 wherein Ra is C1.6 alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR 3 4 , -SR 3 , -C(=0)NR 34
R,
35
-NR
34
R
35 , -NR 34 C(=0)R 35 , or -NR'SO 2 R". Another embodiment of the invention is a compound of Formula lIlA, lIlA-1, IIIA-2, IIIA-3, or a 34 IlA-4 wherein Ra is C1.6 alkyl, wherein said alkyl may be substituted by one or more -OR 15 Another embodiment of the invention is a compound of Formula lilA, IlA-1, IIIA-2, IIIA-3, or R21 R3 R 3 IIIA-4 wherein Ra i Rio , R 2 R" RR3R /Q 3
R
2
R
3 , or R 2 Another embodiment of the invention is a compound of Formula lIlA wherein:
R
3 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 20 2,2-dimethylpropyl, 1-hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, 16 WO 2009/016498 PCT/IB2008/002046 isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR 34 , -SR34, -C(=0)NR14R", 5 -NR'R", -NR"C(=O)R", or -NR"SO 2 R , and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperaziny, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R 2 , R 3 , R 4 , R 5 , R 10 , R", and R 21 ; 10 W is phenyl-(CI-e alkylenyl), pyridyl-(Cre alkylenyl), or indolyl-(C-e alkylenyl), wherein said Cj 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 dimethylethylene, 1 -pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1 -hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 30 and R 3 ' Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 15 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; L is triazolyl, tetrazolyl, or oxadiazolyl; R is H, -(COI alkylene)R6, -C(=O)R 9 , or -S0 2 R , wherein said CIe alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dimethylethylene, 1-pentylene, 2 20 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 31 ;
R
5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more 25 R substituents;
R
7 is methyl, ethyl, 1-propy), 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, -NHR 24 , or -OR 25 , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; 30 R 9 is -(C1. alkylene)R 2 3, -NHR 24 , or -OR 25 ; R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R1 2 may be substituted by one or more substituents selected from CN, -OR 23 , -S0 2 R", -NR 6 R", -NR 24
C(=O)R
23 , and -NR 24 S0 2
R
2 , provided that any one carbon atom of R is not substituted by more than one CN or more than one -OR2; 35 R, RC, R, R 20 , R 22 , R 24 , R 25 , R 33 , R 3 4 , and R 35 are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-penty), 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; R is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; 40 R is H, OH, F, Cl, Br, NH 2 , or SH; 17 WO 2009/016498 PCT/IB2008/002046
R
2 9 is H, -C(=O)CH 3 , -C(=0)CH 2
CH
3 , -C(=O)(CH 2
)
2
CH
3 , -C(=O)CH(CH 3
)
2 ,
-C(=O)(CH
2
)
3
CH
3 , -C(=O)CH(CH 3
)CH
2
CH
3 , -C(=O)CH 2
CH(CH
3
)
2 , -C(=0)(CH 2
)
4
CH
3 ,
-C(=O)CH
2
CH(CH
3
)CH
2
CH
3 , -C(=O)CH 2
C(CH
3
)
3 , or -C(=O)(CH 2 )sCH 3 ; R is Cl, Br, -OR3, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 5 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2
CH
2 OR2;
R
32 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R 32 may be substituted with one, two, or three F;
R
3 6 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1 -hexyl; and 10 R 3 7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyi, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; or a pharmaceutically-acceptable salt thereof. Another embodiment of the invention is a compound of Formula lIlA, lIlA-1, IIIA-2, IIIA-3, or 15 IIIA-4 wherein Y is methyl. Another embodiment of the invention is a compound of Formula IV: 0 N G H N / Rc Y IV wherein G is (C1.3 alkylenyl)-R" or Ra, wherein said C13 alkylenyl may be substituted by one or more substituents selected from OH and F; 20 Ra is C 1 _ alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C1.6 alkyl may be substituted by one or more substituents selected from F, -OR3, -SR4, -C(=O)NR 34
R
35 , -NR' R1, -NR'C(=O)R", or -NR 34 S0 2
R
36 , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R 2 , R 3 ,
R
4 , R 5 , R 10 , R", and R 21 ; 25 W is phenyl-(Cre alkylenyl), pyridyl-(Cr alkylenyl), or 9-membered heteroaryl-(Cr alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R 30 and R 31 ; Y is Cj% alkyl, Cr- haloalkyl; or C-6 hydroxyalkyl; L is 5-membered heteroaryl; 30 R2 is H, F, CN, -OR', R , -C(=O)R', -NRR 3, -NR 8
C(=O)R
9 , -NR"S0 2
R
6 , or -SO 2 R'; R3 is H, F, CN, or -OR2;
R
4 is H, -(Cse alkylene)R 6 , -C(=O)Rg, or -SO2R2;
R
5 is H or -(Coe alkyl), wherein said Cj, alkyl may be substituted by one or more R2 substituents; 0
R
23 623 S2 37,-N 24C ) 23,-N 24 37, N-N 35 R6 is H, CN, -OR , -SO 2 RS, -NR2C(=0)R , -NR2SO 2 R , or 18 WO 2009/016498 PCT/IB2008/002046 R' is -(Cie alkyl), -(CIe haloalkyl), -(C1. alkylene)OH, -NR"R", -NHSO 2
CH
3 , or -OR; 25 R9 is -(C1.6 alkylene)R 2, -NHR 2, or -OR2;
R
0 is H, F, CN, R 1 2 , or -C(=O)R 7 ; R" is H, F, CN, -OR 5 , R 12 , -C(=O)R 7 , -NR 8
R
33 , -NRBC(=O)R 9 , -NR"S0 2
R
36 , or -SO 2
R
2 ; 5 R 1 2 is -(CI- alkyl), wherein said C 1
.
6 alkyl may be substituted by one or more substituents selected from CN, -OR , -SR , -SO 2 R , -NRR 3, -NR 24
C(=O)R
2 1, and -NR 4SO 2 R , provided that any one carbon atom of said C1_ alkyl is not substituted by more than one CN or more than one -OR2; Rb, Rc, R 8 , R 20 , R 2 2 , R 24 , R 2 1, R 33 , R 3 4 , and R 3 5 are independently H or -(Ce6 alkyl); 10 R" is H, F, or R 1 2 ; R1 3 is H, -(CO16 alkyl), or -(C1-6 alkylene)OH;
R
26 is H, OH, halo, NH 2 , or SH;
R
28 is H, NH2, or -OR 29 ; R29 is H, (C_ alkyl), or -C(=O)(COe alkyl); 15 R 30 is H or F;
R
3 is F, Cl, Br, -CN, -C(=O)NH 2 , -OH, -OR , -OCH 2
CH
2 OR , R 3 , ,or (CO alkyl) optionally substituted by -OR or -OCH 2
CH
2 OR2 where R 30 and R 31 when adjacent may be taken together to constitute a group of the formula O-(CH 2 )n- or -O-(CH 2 )n-O-; 20 n is 1 or 2;
R
3 2 is -(C1.6 alkyl) optionally substituted with one, two, or three F;
R
3 6 is -(Ci. alkyl) or -(C3.6 cycloalkyl); and
R
37 is -(C . alkyl), -(C3.6 cycloalkyl), or -(C1.6 alkylene)OH;
R
38 and R 39 are independently H, -(CI- alkyl), or R 3 8 and R 39 taken together form a 5- or 6 25 membered heterocycloalkyl; or a pharmaceutically-acceptable salt thereof. Another embodiment of the invention is a compound of Formula IVA: 0 W'N L Ra H I N / R Re Y IVA wherein Ra, Rc, W, Y, and L are as defined hereinabove for Formula IV. 30 Another embodiment of the invention is a compound of Formula IVA wherein L is triazolyl, tetrazolyl, or oxadiazolyl. Another embodiment of the invention is a compound of Formula IVA wherein L is H NO -N 1 N NA N :N -Ns N -N N -O O'-N NN NN N ,or 9, or 19 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula IVA wherein L is N NN N N- NN- ,or Another embodiment of the invention is a compound of Formula IVA-1 o N:N\ W, N N N a H N N / Re Y IVA- 1 5 wherein Ra, Rc, W, Y, and L are as defined hereinabove for Formula IV. Another embodiment of the invention is a compound of Formula IVA-2 O N -,\ W, N N N Ra H | N /- Rc Y IVA-2 wherein R, Rc, W, Y, and L are as defined hereinabove for Formula IV. Another embodiment of the invention is a compound of Formula IVA-3 O N! N\ W, N N Ra H I N Rc 10 Y IVA-3 wherein R3, RC, W, Y, and L are as defined hereinabove for Formula IV. Another embodiment of the invention is a compound of Formula IVA-4 O N.-O W, NN N R H | N / Re IVA-4 wherein Ra, Rc, W, Y, and L are as defined hereinabove for Formula IV. 15 Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or 0 N -R21 R3 N, IVA-4 wherein Ra is C1.6 alkyl, RIO R 2
R
4 R4 20 WO 2009/016498 PCT/IB2008/002046
R
3 R21 R0 O R 10
R
10
R
21
R
2
R
3
R
5 NN
R
3 0 , O /0 / 1/ R N-R 5 N- R 5 R 0 , or 0 ,wherein said alkyl may be substituted by one or more substituents selected 5 from -OR3, -SR3, -C(=O)NR 3 4 R", -NR 34
R
35 , -NRC 34 (=O)R", or -NR"S0 2 R1 5 Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or 0 R21 R 3 N IVA-4 wherein Ra is Coe alkyl, R 10
R
2 ,4
R
3 R R11, R2 R3 , or R2 , wherein said alkyl may be substituted by one or more substituents selected from -OR', -SR', -C(=0)NR 34 R , -NR R", -NR C(=O)R", 10 or -NR 34
SO
2 R . Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or IVA-4 wherein Ra is C1_ alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR , -SR 34 , -C(=0)NR 3 4 R , -NR R , -NR C(=0)R 35 , or -NR 3 4 S0 2
R
35 . Another embodiment of the invention is a compound of Formula (VA, IVA-1, IVA-2, IVA-3, or 15 IVA-4 wherein Ra is C1_ alkyl, wherein said alkyl may be substituted by one or more -OR3. Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or R21 R3 R 3 IVA-4 wherein Ra is R /0 R 2 R 0 R 3
R
2
R
3 , or R 2 R 21 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or O/ IVA-4 wherein Ra is 0 R 10 , or /Iq R 2
R
2 is CH(CH 3 )OH, C(CH 3
)
2 0H, -NR 8
C(=O)(C
1 .- alkylene)R 2 , or -NR'S0 2
R
3 ; 5 R 1 0 is CH(CH 3 )OH, or C(CH 3
)
2 0H; and R" is CH(CH 3 )OH, C(CH 3
)
2 0H, -NR 8
C(=O)(C
1 .e alkylene)R 2 3, or -NR 8 S0 2
R
3 5 . Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or IVA-4 wherein Y is methyl. Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or 10 IVA-4 wherein W is phenyl-(C 1
-
6 alkylenyl), wherein said phenyl is substituted by one or more groups selected from R 30 and R 31 Another embodiment of the invention is a compound of Formula IVA, IVA-1, IVA-2, IVA-3, or IVA-4 wherein W is phenylmethyl, wherein said phenyl is substituted by one or more groups selected from R 3 0 and R . 15 Another embodiment of the invention is a compound shown in Table 2. Table 2 Compound Name Structure (1 r,4r)-4-((5-(2-((4-fluorobenzyl)carbamoyl)-6- F methylpyridin-4-yl)-2H-tetrazol-2- N yl)methyl)cyclohexanecarboxylic acid /\N'N NH ' OH \ 0 0 N N-(3-methoxybenzyl)-4-(2-(((2R,5S)-5- NN O (hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H- N , tetrazol-5-yl)-6-methylpicolinamide NH O "--OH O N (1 r,4r)-4-((5-(2-((4-fluoro-3- F methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- N 2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic O N'N acid -~ NH 0 N 22 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a compound of Formula I, 11, Ill, or IV wherein: G is -CH 2 R", -CH 2
CH
2 R", -CH(Ra)CH 3 , -CH 2
CH
2
CH
2 Ra, -CH 2
CH(CH
3 )Ra -CH(Ra)CH 2
CH
3 , or Ra, wherein said CH, CH 2 , and CH 3 groups may be substituted by one or more 5 substituents selected from OH and F; Ra is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1 -hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyt, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 10 wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR", -SR34, -C(=O)NR34R 35 , -NR 3 4
R
35 , -NR 3 4 c(=0)R 35 , or -NR34S0 2
R
3 6 , and wherein said aziridinyl, azetidiny, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, 15 tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R2, R3, R4 , R , R 11 , and R 21 ; W is phenyl-(Cr alkylenyl), pyridyl-(C- 6 alkylenyl), or indolyl-(C- 6 alkylenyl), wherein said C1. 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 20 dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R and R3; Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; 25 L is triazolyl, tetrazolyl, or oxadiazolyl; 4 6 912 R' is H, -(C 1 6 alkylene)R , -C(=O)R9, or -SO 2 R , wherein said C,.e alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dimethylethylene, 1-pentylene, 2 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is 30 31. substituted by one or more groups selected from R and R ; 30 R 5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more
R
2 6 substituents;
R
7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 35 2,2-dimethylpropyl, 1-hexyl, -NHR 2 4 , or -OR 2 , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; R is -(C1.6 alkylene)R , -NHR 24, or -OR21 R1 2 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 40 2,2-dimethylpropyl, or 1-hexyl, wherein R' 2 may be substituted by one or more substituents selected 23 WO 2009/016498 PCT/IB2008/002046 from CN, -OR 2 3 , -S0 2
R
37 , -NR 8 R3, -NR 24 C (=O)R 23 , and -NR 24 S0 2
R
23 , provided that any one carbon atom of R is not substituted by more than one CN or more than one -OR2; Rb, Rc, R , R , R R24, R2 , R , R34, and R are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; 5 R 23 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; R 26 is H, OH, F, Cl, Br, NH 2 , or SH; R 2 is H, -C(=O)CH 3 , -C(=O)CH 2
CH
3 , -C(=O)(CH 2
)
2
CH
3 , -C(=O)CH(CH 3
)
2 , 10 -C(=O)(CH 2
)
3
CH
3 , -C(=O)CH(CH 3
)CH
2
CH
3 , -C(=O)CH 2
CH(CH
3
)
2 , -C(=O)(CH 2
)
4
CH
3 ,
-C(=O)CH
2
CH(CH
3
)CH
2
CH
3 , -C(=O)CH 2
C(CH
3
)
3 , or -C(=O)(CH 2
)
5
CH
3 ; R 1 is Cl, Br, -OR , methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2
CH
2 OR2;
R
3 2 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 15 2,2-dimethylpropyl, or 1-hexyl, wherein R may be substituted with one, two, or three F;
R
3 6 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-buty), 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl; and
R
37 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 20 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; or a pharmaceutically-acceptable salt thereof. Another embodiment of the invention is a compound shown in Table 3. Table 3 Example Compound Name N 0. 1. N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)pyrimidine-4-carboxamide 2 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4 ((methylsulfonyl)amino)cyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 3. N-(3-Chloro-4-fluorobenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)pyrimidine-4-carboxamide 4 N-(3-Chloro-4-fluorobenzyl)-6-(2-((trans-4 ((methylsulfonyl)amino)cyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidineOl -4-carboxamide 5. N-(3-Methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 24 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 6 N-(3-Methoxybenzyl)-2-methyl-6-(2-(((trals-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yI )pyrimidine-4-carboxamide 7 N-(3-Methoxybenzy)-6-(2-((trals-4-acetamidocycIohexyl)methyl)- 2
H
tetrazol-5-yl)-2-methylpyrimidine-4-carboxarnide 8 N-(3-Methoxybenzyl)-6-(2-(((trafls)-4-(2 h ydrox yace tam ido)cyclohexyl)meth yl)-2H-tetrazol-5-A y)-2 methylpyrimidine-4-carboxamide 9. N-(4-Fluoro-3-methoxybenzyl)-6-(2-(tras-4-amiocyclohexy)methyI) 2H-tetrazo1-5-yl)-2-methylpyrimidine-4-carboxamide 10 N-(4-Fluoro-3-methoxybenzy)-2-methyl-6-(2-((trals-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yI )pyrimidine-4-carboxamide 11 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trafls-4 acetamidocyclohexyl )methyl )-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 12 N-(4-Fluoro-3-methoxybeflzyl)-6-(2-(((trafls)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 13. N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trafls)-4 am inocyclohexyl)methyl)-2 H-tetrazol-5- yl)-2-m ethyl pyrilhid ife-4 carboxamide 14 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trals)-4 acetam idocyclohexyl )methyl )-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 15 N-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2-(((trals)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yI )pyrimidine-4-carboxamide 16 N-(3-(2-Hydroxyethoxy)beflzyl)-6-(2-(((trals)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yI )-2 m ethyl pyrim idin e-4-carboxa mide 17 N- (4 -Flu oro-3-(2 -hydroxyethoxy)be nzy()-6-(2-(((trafls)-4 acetamidocyclohexyl )methyl )-2H-tetrazol-5-yI)-2 methylpyrimidine-4-carboxamide 18 N-(4 -Fl uoro-3-(2 -hyd roxyethoxy)beflzyl)- 2-ml'ethyl -6-(2 -(((tTrfls)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 19 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trals)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 20. trans-Methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 m ethyl pyrim id in-4 -yl)-2 H-tetra zol-2 yl )meth yl)cyc loh exanecarboxyl ate 25 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 21 trans-4-((5-(6-((4-Fluoro-3-methoxybenzy)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid 22. (trans)-Methyl 4-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate 23 (trans)-4-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl) 2H-tetrazol-2-yl)methyl)cyclohexanecarboxyic acid 24 N-(3-Methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 25 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 26 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4 cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methy)pyrimidine-4 carboxamide 27 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans-4 cyanocyclohexyl)methyl)-2H-tetrazol-5-y)-2-methylpyrimidine-4 carboxamide 28 N-(3-Methoxybenzyl)-6-(2-(((trans)-4-hydroxy-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 29 N-(3-Methoxybenzyl)-6-(2-(((cis)-4-hydroxy-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 30 N-(3-chloro-4-fluorobenzyl)-6-(2-((trans-4-hydroxy-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-y)-2 methylpyrimidine-4-carboxamide 31. rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3 aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine 4-carboxamide 32 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3 acetamidocyclopentyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 33 (+)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3 acetamidocyclopentyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 34 (-)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 R*,3S*)-3 acetamidocyclopentyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 35 rac-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3R*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 36 (+)-N-(4-FIuoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 R*,3S*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 26 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 37 (-)-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((( 1 S,3R*)-3 (m ethyl su Ifonam ido)cycIopeltyi)m eth yl)-2 H-tetrazol -5 yl)pyrimidine-4-carboxamide 38. N-(3 -Methox ybenzy))-2-m ethyl-6-(2 -((S)-m oTphohln-2 -yl methyl)-2 H tetrazol-5-y))pyrimidine-4-carboxamide 39 N-(3-Methoxybenzyl)-6-(2-(((S)-4-aCetylmorphohl-2-yI)methyI>-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxarnide 40 NV-(3-Methoxybenzyl)-2-methy-6-(2-(((R)-4-(ethylsulfofyl)morpholifl 2 yI)methyl)-2H-tetrazol-5-yi)pyrimidine-4-carboxamide 41. N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S)-morpholifl-2-ylmethyI) 2H-tetrazol-5-yi)pyrimidine-4-carboxamide 42 N-4fur--ehxbny)6(-(S--ctlopoi--lm ty) 2 H-tetrazol- 5-y)-2-m ethyl pyrim id ife-4-carboxam ide 43 N-(4-Fluoro-3-methoxybenzyl)-2-mlethyI-6-(2-(((R)- 4 (methylsulfonyI)morpholin2-y)methy)-2H-tetazol-5 yl)pyrimidine-4-carboxamide 44. N-(3-Methoxybenzy)2-methyl-6-(2-((R)-morphoil-2-ylmethyI )-2H tetrazol-5-yl)pyrimidifle-4-carboxamide 45 N-(3-Methoxybenzy)-6-(2-(((R)-4-acetyflmorpholifl-2-yl)methyl)-2H tetrazol -5-y).2-m ethyl pyrim id ine4-carboxalhide .46 N-3Mtoyezi--ehl6(-(()4(ehlufnlmrhln2 yI)mnethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamlide 47. N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholil-2-ylmethyl) 2H-tetrazol-5-yl)pyrimidine-4-carboxamide 48 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-(((R)-4 (methylsulfonyl)morphoin-2-y)methyl)-2H-tetrazol-5 ylpyrimidine-4-carboxamide 49, N-(3-Ethyl-4-fuorobeflzyl)-2-methyl-6-(2-((S)-morpholifl2-ylmethyI )-2H tetra zol- 5-yl)pyri mid ine4-carboxalhide 50 N -(3- Eth yi-4-Aluoro ben zyl)-2-n'ethyl -6-(2-(((R)-4 (methylsufonyl)morpholin-2-yl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 51 rac-6-(2-((1 ,4-Dtoxan-2-yI)methyl)-2H-tetrazol-5-yI)-N-(3 methoxybenzyl)-2-methylpyrimidfle-4-carboxamide 52 rac-6-(2-(( 1 4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fIuoro-3 methoxybenzyl)-2-methylpyrimidile-4-carboxamide 53 6-(2-(((R)-1 ,4-dioxan-2-y)mlethyl)-2H-tetrazol-5-YI)-N-(3 m ethoxybenzyl)-2 -m ethyl pyrim id ie-4 -carboxam ide 54 6-(2-(((R)- 1,4-dioxan-2-y)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimlidifle-4-carboxamide 27 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 55 6-(2-(((R)- 1,4-dioxan-2-y)methyl)-2H-tetrazo-5-y)-N-(3-chloro-4 fluorobenzyl)-2-methyipyrimidine-4-carboxamide 56 6-(2-(((R)- 1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-y)-N-(4-fluoro-3-(2 hydroxyethoxy)benzy)-2-methylpyrimidine-4-carboxamide methoxybenzyl)-2-methylpyrimidine-4-carboxamide 58 6-(2-(((S)- 1,4-dioxan-2-y)methyl)-2H-tetrazol-5-y)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimidine-4-carboxamide 59 6-(2-(((S)-1 ,4-dioxan-2-yI)methyl)-2H-tetrazol-5-y)-N-(3-chloro-4 fluorobenzyl)-2-methylpyrimidine-4-carboxamide 60 6-(2-(((S)- 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-y)-N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-2-methylpyrimidine-4-carboxamide 61 ra--3Mtoyezy)6(-(2*5*)5(yrxmt 1 ,4-dioxan 2-yI)methyl)-2H-tetrazol-5-y)-2-methylpyrimidine-4-carboxamlide 62 N-(3-Methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)- 1,4-dioxan-2 yI )methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 63 N-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1 ,4-dioxan-2 yI )methyl)-2H-tetrazol-5-yI)-2-methylpyrimidirie-4-carboxamide 64 ra--4Fur--ehxbny)6-2((SR)5(yrxmty) 1 ,4 -d ioxa n-2- yI)m eth yI)-2 H- tetrazoI- 5-yl)-2-m ethyl pyrim id ine-4 carboxamide 65 N-(4-Fluoro-3-metlioxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1 ,4 dioxan-2-yl)methyl)-2H-tetrazo-5-y )-2-methylpyrimidine-4 carboxamide 66 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)- 1,4 dioxan-2-yI)methyl)-2H-tetrazol-5-y )-2-methylpyrimidine-4 carboxamide 67 ra--4Furo3mtybny -- 2(S, 5R*)-5-(hydroxymethyA)-1 .4 dioxan-2-yI)methyl)-2H-tetrazol-5-yl )-2-methylpyrimidine-4 carboxamide 68 N-(4 -F luoro- 3-meth yl ben zyl )-6- (2-(((.2S, 5R)- 5-(hyd roxymeth yl)- 1, 4 dioxan-2-yl)methyl)-2H-tetrazol-5-yI)-2-methylpyrimidine-4 carboxamide 69 N-(4-Fluoro-3-methylbenzyl )-6-(2-(((2R,5S)-5-(hydroxymethyl)- 1,4 dioxan-2-yI)methyl)-2H-tetrazol-5-yI)-2-methylpyrimidine-4 carboxamide 70 rac-N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-(2-(((2S,5R*)-5 (hyd roxym ethyl)- 1 ,4-d joxa n-2 -yl)m ethyl)-2H-tetrazol -5-yl )-2 methylpyrimidine-4-carboxamide 71 rac-N-(3-Ethyl-4-fluorobenzyI)-6-(2-(((2 S*,5R'*)-5-(hydroxymethyI)- 1,4 dioxan-2-yI)methyl)-2H-tetrazol-5-y )-2-methylpyrimidine-4 carboxamide 72 N-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymlethyl)- 1,4-dioxan 2 -yI )methyl)-2H-tetrazot-5-yI)-2-methylpyrimidine-4-carboxamide 73 N-(3-Ethyl-4-fluorobenzyl )-6-(2-(((2R,5S)-5-(hydroxymethyl)- 1 4-dioxan 2-yI)methyl)-2H-tetrazol-5-yI)-2-methylpyrimidine-4-carboxamfide 74 rac-N-(4- Fl uoro-3-isopropyl ben zyl)6( -(( * *-5( drxmehy) 1 ,4-dioxan-2-yI)methyl)-2H-tetrazol-5-yi)-2-methylpyrimidifle-4 carboxamide 28 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 75 rac-N-(3-Cyclopropy-4-fluorobezl)-6-(2-(((2S,5R) 5 (hydroxymethyl)- 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl )-2 methylpyrimidine-4-carboxamide 76 ra-N (3C.n--nooezl--2(( ,5*--hdoy ty) ,4 dioxan-2-yl)methyl )-2H-tetrazol-5-yI )-2-methylpyrimidine-4 carboxamide 77 ra--4Fur--2hdoytox~ezl--2((SR)5 (hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yI)-2 m ethyl pyri mid ine-4-carboxam ide 78 ra--3Clr--lorbny)6(-(2*5R*)-5-(hydroxymethy)- 1,4 dioxan-2-yl)methyl)-2H-tetrazo-5-y)-2-methylpyrimi'difle- 4 carboxamide 79 N-3Clr--loobny)6(-(2 R)5(yrxmty)1,4 dioxan-2-yl)methyl)-2H-tetrazo-5-yl)-2-mlethylpyrimlidifle- 4 carboxamide 80 N-3Boo4furbny)6(2 (S5)5(yrxmty)1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimlidifle- 4 carboxam ide 81 N-4-FIur-- drxyeny)6(-(2S R--hdrxmehl-1 4 dioxan-2-yI)methyl)-2H-tetrazol-5-yI )-2-methylpyrimidine-4 carboxamide 82 N-4Fur--ehxbezl 12((R5)--hdoyehl-,4 dioxan-2-y))methyl )-2H-tetrazol-5-yI)-2-methylpyrimidifle-4 carboxamide 83 N-(3-C hloro-4-fl uorobelzyI)-6-(2- ((5,5-bis (hyd roxymethyl)- 1 ,4-dioxan-2 yl)methyI)-2H-tetrazo-5-yl)-2-methylpyrimidile-4-carboxamTide 84 N-(3-Methoxybenzyl).6-(2-((5,5-bis(hydroxymethyl)-1 ,4-dioxan-2 yl )methyl)-2H-tetrazol-5.yl)-2-methylpyrimlidifle-4-carboxamide 85. rac-(2S,5S*)-Methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yI)methy)- 1,4-dioxane-2 carboxylate 86 ra-2S,5S) -(5(-(-Mtoyezlcramol-- ty yimdi 4-yI)-2H-tetrazol-2-yI)methyl)-1 ,4-dioxane-2-carboxylic acid 87. rac-(2 8 ,5S*)-methyl 5-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoy )-2 methylpyrimidin-4-y)-2H-tetrazol-2-YI)methyl)-l ,4-dioxane-2 carboxylate 88 rac-(2S*,S)5(5(6(4Fur--mtoyezl~abmy)2 methylpyrimidin-4-yI )-2H-tetrazol-2-yl)methyl )- 1,4-dioxane-2 carboxylic acid 89 (2S,5S)-5-((5-(6-((4-Fluoro-3-methoxybelzyl)carbamoyl)-2 methylpyrim id in-4 -yl)-2 H-tetrazol-2 -yl)m ethyl)- 1,4-d ioxa ne-2 carboxylic acid 90 (2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamlY)-2 meth ylpyrim id in-4 -yl)-2 H-tetrazo -2 -yl)m ethyl)- 1,4-d ioxane-2 carboxylate 29 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 91 N-(4-Fluoro-3-methoxybenzyi)-6-(2-(((2S, 5S)-5-(2-hydroxypropan-2-y) 1 ,4-dioxan-2-yI)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidifle-4 carboxamide 90. (2.S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrim idin-4 -yl)-2 H-tetrazol-2-yl)m ethyl)- 1,4-d ioxane-2 carboxylate 91. N-(4-Fluoro-3-methoxybenzyl )-6-(2-(((2S,5S)-5-(2-hydroxypropan-2-y) 1 ,4-dioxan-2-yI)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidifle-4 carboxamide 92, rac-(2 S',5S*)-Methyl 5-((5-(6-((3-chloro-4-fluorobenzyl )carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2 carboxylate 93 rac- (2 S* ,5S*)-5-((5-(6-((3-C hl oro-4 -flu oroberizyl)carbam oyl)-2 m ethyl pyrim id in-4 -yI )-2H-tetrazol -2 -yl)meth yi)- 1 ,4 -dioxa ne-2 carboxylic acid 94. rac-(2S*,5S*)-MethyI 5-((5-(6-((3-bromo-4-fluorobenzyl)carbamoyl)-2 methylpyrimidin-4-yI)-2H-tetrazoi-2-yI)methyl)- 1,4-dioxane-2 carboxylate 95 rac- (2 S*, 5 *-5(5(-(-rmo4-fuooezlcramol methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dioxane-2 carboxylic acid 96. ra--3Mtoyezy)6(-(2*5*)5(mnmt 1 ,4-dioxan 2-yi)methyi)-2H-tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide 97 ra--3Mtoyezy)6(-(2*5*-5(ctmdmt 1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide 98 rac-N-(3-Methoxybenzyl) -2((2*5*--(ctmd1ehl-,4 dioxan-2-yI)methyl )-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide 99 N-(4 -F luoro-3-methox yben zyl)--2(( R* R) -hdrxr ty) tetrahydro-2H-pyran-2-y )methyl)-2H-tetrazol-5-yI)-2 m ethyl pyrim id ine-4-ca rboxam ide 100 N-4Fur--ehxyez -- 2((R,5R*)-5-(hydroxymethy) tetra hydro-2 H- pyra n-2-y )meth yl)-2 H-tetrazol -5- yl)-2 methylpyrimidine-4-carboxamide 101 N-4-Fur--mehxbnzl--2 (( * *-5(y oy ty) tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2 methyipyrimidine-4-carboxamide 30 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 102 N-(4-fluoro-3-methoxybenzyl) -2((S*5*--hdrxmty) tetra hydro-2 H-pyra n-2 -y)meth yl)-2H-tetrazol -5-y)-2 methylpyrimidine-4-carboxamide 103 N-3Mtoyezl--2-(2*5*--yrx-ttayr-Hprn2 yI )m ethyi)-2H-tetrazol- 5-yl)-2-m ethyl pyrim id ine-4 -carbOXalhide 104 N-3Mtoyezl--2((RS)5hdoyttayr-Hprn2 yi)methyl)-2H-tetrazol-5-yI).2-methylpyrimidine-4-carboxamide 105 (+--4Fur--ehxbnyl--2((RS)5hdoy tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yi)- 2 methylpyrimidine-4-carboxamide 106 (---4Fur--ehxbny)6(-(2 *5 *--yrx-erhdo 2H-pyran-2-yl)methyl)-2H-tetrazol-5-y)-2-methylpyrimidifle-4 carboxamide 107 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R5S)-5-hydroxy-5 (hydroxymethyl).tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide 108 rac.N-(4-Fluoro-3-methoxybenzyl) -2((2*5*--hdoy5 (hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxarmide 109 rac-N-(3-Methoxybenzyl)-6-(1 -(((2R* ,5S*)-5-(hydroxymethyl)- 1,4-dioxan 2-yI)methyl)- 1 H-i ,2,4-triazol-3-yl)-2-methylpyrimidine-4 carboxamide 110. N-(3-Methoxyberizyl)-6-( 1 -((trans -4 -am inocyclohexyl)methyl1 H- 1,2,4 triazol-3-yl)-2-methylpyrimidmne-4-carboxamide ill N-(3-Methoxybenzyl)-6-(1 -(((trans)-4-acetamidocyclohexyl)methyl)-1I
H
1, 2,4-triazol- 3-yl)-2-m ethyl pyrim id ine-4 -carboxam ide 112 N-(3-Methoxybenzyl)-2-rnethyl-6-(I -(((trans)-4 (methylsulfonamido)cyclohexyl)mlethyl)-1 H-i.2 ,4-triazol-3 yl)pyrimidine-4-carboxamide 113, 2-((trans)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidifl yl)-l H-i ,2,4-triazol- I -yI)methyl)cyciohexylamino)-2-oxoethyl acetate 114 N-(3-Methoxybenzyl)-6-(l 1 ((trans)-4-(2 hydroxyacetam ido)cycloh exyl)m ethyl)- 1 H-i ,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide 115 rac-N-(4-Fluoro-3-methoxybenzyl)-6-( 1-(((2R'*,5S*)-5-(hydroxymethyi) 1 ,4-dioxan-2-yl)methyl)- 1 H-i ,2,4-triazol-3-yI)-2 methylpyrimidine-4-carboxamide 116. N-(4-Fluoro-3-methoxybenzyl)-6-( 1 -((trans-4-aminocyclohexyl)methyl
)
1 H-i ,2,4-triazol-3-yI)-2-methylpyrimidifle-4-carboxarflide 117 N-(4-Fluoro-3-nlethoxybeflzyl)-2-mlethyl-6-( 1 -((trans-4 (m ethyl sulIfonam id o)cyclohexyl)m ethyl)- 1 H-i ,2,4-triazol-3 yl)pyrimidine-4-carboxamide 31 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 118 N-(4-fluoro-3-methoxybenzyl)-6-(1 -((trans-4 acetamidocycohexyl)methy)- 1 H-i ,2,4-triazol-3-yI)-2 methylpyrimidine-4-carboxamide 119 N-(4-Fluoro-3-methoxybenzyl)-6-( 1 -((trans-4-(2 hydroxyacetamido)cyclohexyl)methyl)- 1 H- 1,2 ,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide 120 N-(4-Fluoro-3-(2-hydroxyethoxy)befly)-2-methYl-61 1 -((trans-4 (methylsulfonamido)cycohexyl)methyl)- 1 H- 1,2 ,4-triazoI-3 yl)pyrimidine-4-carboxamide 121 N-(4-Fluoro-3-(2-hydroxyethoxy)belzyl)-6-( 1 -((trans-4 acetamidocyclohexyl)methyl)-l H-i.2 ,4-triazol-3-yt)-2 methylpyrimidine-4-carboxamide 122. N-(4-Fiuoro-3-methoxybenzyl)-6-(5-((trans-4-amiocycilohexyi)methy) 1, 2,4-oxad iazol-3- yl)-2-m ethyl pyri mid ine-4-ca rboxam ide 123 N-(4-fluoro-3-methoxybeflzyl)-6-(5-((trafls-4 aceta midocyclohex yl)m ethyl)- 1, 2,4 -oxad iazol-3-yi)-2 methylpyrimidirie-4-carboxamide 124 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(5-((trals-4 (methyl s ulfonam ido)cycloh exyl)m ethyl )- 1, 2,4 -oxad ia zol -3 yi)pyrimidine-4-carboxamide 125 N-(4-Fluoro-3-methoxybenl)-6-(2-(3-hydroxypropy)-2H-tetrazoF-5-yI) 2-methylpyrimidine-4-carboxamide 126 N-(4-Fluoro-3-methoxybe1zyl)-6-(2-((S)-3-hydroxy-2-methyIpropyl)-2H tetra zol- 5-yI)-2-m eth ylpyrim id ine-4 -carboxam ide 127 N- (4 -F Iu oro-3-m ethoxybenzyl)-6-(2 -((R)-3-hydroxy-2 -m ethyl propyl)-2 H tetra zol-5-yI)-2-m ethyl pyrim id ine-4 -ca rboxam ide 128 N-(4-Fluoro-3-methoxybenzyl )-6-(l1-(((2S,5R)-5-(hydroxymethyl )- 1,4 dioxan-2-yI)methyl)-1 H-i .2 ,3-triazol-4-yl)-2 -m ethyl pyri mid ine-4 carboxamide 129 N-(4-Fiuoro-3-methoxybenzyl)-6-( 1 -(((S)-4 -acetylmorphol in-2 -yl)meth'yl) 1 H- 1,2 ,3-triazol-4-yI)-2-methylpyrimidine-4-carboxamide 130. N-(3-Methoxybenzyl)-2-methyi-6-( 1 -((S)-mnorphoiin-2-yimnethyl)- 1 H- 1,2,3 triazol-4-yI)pyrimidine-4-carboxamide 131 N-(3-Methoxybenzyl)-6-( 1 -(((S)-4-acetylmorpholin-2-yI)methyl)-I H- 1,2,3 triazol-4-yl)-2-methylpyrimidine-4-carboxamlide 132 N-(3-Methoxybenzyl)-2-methyl-6-( 1 -(((R)-4-(methylsulfonyl)morpholifl-2 yl)methyl)- 1 H-i ,2,3-triazol-4-yl)pyrimidine-4-carboxamide 133 N-(3-Methoxybenzyl)-6-(l1-(((2S,5R)-5-(hydroxymethyl)- 1,4-dioxan-2 yl)methyl)- 1 H-i ,2,3-triazoi-4-yI)-2-methylpyrimidine-4 carboxamide 134. N-(4-Fluoro-3-methoxybenzyl )-6-( I -(((trans)-4-aminocyclohexyl)methyl) 1 H-i ,2 ,3-triazol-4-yI)-2-methylpyrimidine-4-carboxamnide 32 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 135 N-(4-Fluoro-3-methoxybenzyl)-6-(l -(((trans)-4 acetamidocyclohexyl )methyl )- 1 H- 1,2 ,3-triazol-4-yI)-2 methylpyrimidine-4-carboxamide 136 N-(4-Fiuoro-3-methoxybelzyl)-6-( 1 -(((trans)-4-(2 hydroxyacetamido)cycIohexyI)methyl)-1 H-i ,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide 137. N-(4-Fluoro-3-methoxybenzyl )-6-( 1 -(((1 R,3S)-3 am inocyclopentyl)m ethyl)- 1 H- 1,2 ,3-triazol-4-yI)-2 methylpyrimidine-4-carboxamide 138 N-(4-Fluoro-3-methoxyberizy)-6-(1 -(((1 R,3S)-3 acetamidocyclopentyl )methyl )- 1 H-i ,2,3-triazol-4-yI)-2 methylpyrimidine-4-carboxamide 139 N-(4-fluoro-3-methoxybenzyl)-6-( 1 -(((1 R,3S)-3-(2 hydroxyacetamido)cyclopentyt)methyl)- 1 H- 1,2 ,3-triazol-4-yt)-2 methylpyrimidirie-4-carboxamide 140 N-(4-Fluoro-3-methoxybeizyl)-2-rnethYl-6-( 1 -(((1 R,3S)-3 (methylsulfonamido)cyclopentyl)methyl)- 1 H-i ,2,3-triazol-4 yl)pyrimidine-4-carboxamide 141. N-(4-Fluoro-3-methoxybenzyl)-6-( 1 -(((1 S,3R)-3 aminocyclopentyl)methyl)-1 H- 1,2 ,3-triazol-4-yt)-2 methylpyrimidine-4-carboxamide 142 N-(4-Fluoro-3-methoxybelzyl)-6-( 1 -(((I S,3R)-3 aceta midocyclopentyl)m ethyl)- I H-i.2 ,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide 143 N-(4-Fluoro-3-methoxybenzyl )-6-(1 -(((1 S,3R)-3-(2 hydroxyacetamido)cyclopeltyI)mlethyl )- 1 H- 1,2 ,3-triazol-4-yI)-2 methylpyrimidine-4-carboxamide 144 N-(4-Fluoro-3-methoxybenzyl)-2-methy-6-( 1 -(((1 S,3R)-3 (methylsulfonamido)cyclopentyl)methyl)-1 H-i ,2,3-triazol-4 yI )pyrimidine-4-carboxamide 145 6-( 1 -(((S)- 1,4 -Dioxan -2-yI)m ethyl)- 1 H-i ,2,3-triazol-4-yl)-N-(4-fluoro-3 m eth oxybenzyi )-2-m ethyl pyri mid ine-4 -carboxalhide 146 6-( 1 -(((R)- 1 ,4-Dioxan-2-yl)methyl)- 1 H-i ,2,3-triazol-4-y)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimidlfle-4-carboxamide 147. N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-amino-tetrahydro-2H pyran-2-yl)methyl)-i H-i ,2 ,3-triazol-4-yl)-2-methylpyrimidifle-4 carboxamide 148 N-(4-Fluoro-3-methoxybenzyl)-6-(l1-(((2S,5R)-5-acetamido-tetrahydro 2 H-pyran -2-yl)m ethyl)- 1 H-i.2 ,3-triazol-4-yl)-2-methylpyrimidifle 4-carboxamide 33 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 149 N-(4-Fluoro-3-methoxybenzyl)-6-(5-(((2S,5R)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-1,2,4-oxadiazol-3-yl)-2-methylpyrimidine-4 carboxamide 150 6-(5-((2R)-1,4-Dioxan-2-ylmethyl)-1,2,4-oxadiazol-3-y)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimidine-4-carboxamide 151 6-(5-((2S)-1,4-Dioxan-2-ylmethyl)-1,2,4-oxadiazol-3-yl)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimidine-4-carboxamide 152 N-(4-Fluoro-3-methoxybenzyl)-6-(3-(((trans)-4 acetamidocyclohexyl)methyl)isoxazol-5-y)-2-methylpyrimidine 4-carboxamide 153 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yi)-6-methylpicolinamide 154 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 155 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (ethylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 156 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (cyclopropanesulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide 157 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (butylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 158 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)- 2
H
tetrazol-5-yl)-6-methylpicolinamide 159 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-isobutyramidocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 160 2-((trans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl) 2H-tetrazol-2-yl)methyl)cyclohexylamino)-2-oxoethy acetate 161 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 162 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2 methylpropanamido)cyclohexy)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 163 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-((S)-2 hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 164 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 165 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2 methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 166 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3 methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 34 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 167 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 168 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3 hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 169 1 -((trans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-y) 2H-tetrazol-2-yl)methyl)cyclohexyl)-3-methylurea 170 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 171 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 172 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yi)- 6 methylpicolinamide 173 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-( 2 methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 174 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-( 3 methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 175 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 176 2-((trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamino)- 2 oxoethyl acetate 177 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 178 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(3 hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 179 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy- 2 methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 180 N-(3-Ethoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 181 N-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 182 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((trans)4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 183 N-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 35 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 184 N-(3-(2-Hydroxyethoxy)benzy)-6-methy-4-(2-(((tals)-4 (m ethyl s ulfonam ido)cycloh exyl)m eth yl)-2 H-tetrazol -5 yl)picolinamide 185 N-4Fur--eh~ezl--2((rn)4aioylhxlmty) 2H-tetrazol-5-yI)-6-methylpicolinamide 186 N -(4 Aluoro-3- methylibenzyl)-6-fl'eth yi-4 -(2-(((trafls)- 4 (methylsulfonamjdo)cycloIhexyl)methyI)-2H-tetrazoI-5 yl)picolinamide 187 N-(4-Fluoro-3-methylbenzy)-4-(2-(((trafls)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-y)-6 methyipicolinamide 188 N-(4-Fluoro-3-methylbelzyl)-4-(2-(((trals)-4-(3 aminopropanamido)cycohexyl)methyl)-2H-tetrazo-5-yl )-6 methylpicolinamide 189 N-(4-Fluoro-3-methylbelzyl)-4-(2-(((trals)-4-(2 methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 190 2-((trans)-4-((5-(2-((4-Fluoro-3-methylbelzyl)carbamoyi )-6 methylpyridin-4-yl)-2H-tetrazol-2-y)methyl)cyCIohexylamilo)- 2 oxoethyl acetate 191 N-(4 -Fl uoro-3-methyl benlzyl )-4 -(2- (((trans)-4 -(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methyipicolinamide 192 N-(4 -F luoro-3-m ethyl benlzyl )-4 -(2-(((trans)-4 -(3 methoxypropanamido)cyclohexyl)methyl )-2H-tetrazol-5-yl)-6 methyipicolinamide 193 N-(4-fluoro-3-methylbenzyl)-4-(2-(((trafls)-4-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yi )-6 methylpicolinamide 194 N-(3-C h oro-4 -fluoroben zy)-4 -(2 -(((tals)-4 -am iocyc)ohexyl)m ethyl) 2H-tetrazol-5-yi)-6-methylpicolinamide 195 N-(3-Chloro-4-fluorobenzyi)-6-methyl-4-(2-(((trafls)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 196 N-(3-Chioro-4-fluorobenly)-4-(2-(((trafls)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 197 N-(3-Chloro-4-fluorobenzy)-4-(2-(((trals)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl )-6 methylpicolinamidle 198 N-(3-Chloro-4-fluorobelzyl)-4-(2-(((trafls)-4-(2 methoxyacetamido)cyclohexyl )methyl )-2H-tetrazol-5-yl )-6 methylpicolinamide 199 2-(rn)4(5(-(-hoo4furbny~abmy)6mtyprdn 4-yl)-2H-tetrazl-2-yl)lethyl)cyclohexylamilo)-2-oxoethyI acetate 200 N-(3-Chloro-4-fluorobeflzyl)-4-(2-(((trafls)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y )-6 methylpicolinamide 36 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 201 N-(3-C hloro-4 -flu orobeflzyl)-4 -(2 -(((trals)-4-(3 methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)- 6 methylpicolinamide 202 N-(3-Chloro-4-fluoroberlzyl)-4-(2-(((trafls)-4-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 203 N-4Fur--(-yrxehx~ehlbny)6mty--2((rn) 4 -(m ethyl sulfonamnido)cyclohexyl)m ethy)-2 H-tetrazol-5 yI)picolinamide 204 4-(2-(((trafls)-4AcetamidocycIohexyl)methy)-2Htetrazo5y)N-(( 6 hydroxypyridin-2-yl)methyl)-6-methylpicoliflaflde 205 N-(3-(H ydroxymnethyl) ben zy)-4 -(2-(((trals)-4 acetamidocyclohexyl)methyl)-2H-tetrazoi-5-y)- 6 methylpicolinamide 206 N-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((trals)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yI)-6 methyipicolinamide 207 N-(4-Fluoro-3-(hydroxymethyl)bely)-4-(2-(((trafls)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 208 N-(3-Ethoxybenzyl)-4-(2-(((trals)-4-acetamidocyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 209 N-3Mtoyezl--2((i)4aioylhxlmty)2-erzl 5-yi)-6-m ethyl picol inamide 210 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((cis)-4 (methylsulfonamido)cyclohexyl )methyl)-2H-tetrazol-5 yl)picolinamide 211 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-acetmidocyctohexyI)methyl)- 2
H
tetrazol-5-yi)-6-methylpicolinamide 212 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(3 aminopropanamido)cyclohexy)methy)-2H-tetrazo-5-yY)- 6 methylpicolinamide 213 N-(3-Methoxyberizyl)-4-(2-(((cis)-4-(2 methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 methylpicolinamide 214 2-(i)4(5(-(-mtoyez craol)6mtyprdn4y)-2H tetra zol-2 -yl)methyl)cyclo hexylamrino)-2-oxoeth y acetate 215 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yi)-6 methylpicolinamide 216 N-(3-Methoxybenzyl )-4-(2-(((cis)-4-(3 methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)- 6 methylpicolinamide 217 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y )-6 m ethyl picol inam ide 218 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2-hydroxy-2 methylpropanamido)cyclohexyl)methyl)-2H-tetrazo-5-yl)- 6 methyipicolinamide 37 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 219 N-(4-Fluoro-3-methoxybenzy)-4-(2-(((cis)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 220 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2 methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)- 6 methylpicolinamide 221 N-(4-Fuoro-3-methoxybezyl)-4-(2-(((cis)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yJ)-6 methylpicolinamide 222 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((cis)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 223 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 224 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 225 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 226 N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 227 N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-acetamidocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 228 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 229 rac-2-((1 R*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-y)-2H-tetrazo-2-yl)methyl)cyclohexylamino)-2 oxoethyl acetate 230 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 231 N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 232 N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 233 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 234 rac-2-((1 R*,3S*)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamino)-2 oxoethyl acetate 235 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 236 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 38 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 237 N-4Fur--ehxbnyl--2(( *3 *--2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 238 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(3 methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 239 rac-N-(3-Methoxybenzy)-4-(2-(((1 S*,3R*)-3-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y )-6 methylpicolinamide 240 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((( 1 S*,3R*)-3 (methylsulfonamido)cyclohexy)methyl)-2H-tetrazol-5 yl)picolinamide 241 rac-N-(3-Methoxybenzyl)-4-(2-(((I 1 /,3R*)-3-aminocyclohexyl)methy) 2H-tetrazol-5-yl)-6-methylpicolinamide 242 rac-N-(3-Methoxybenzy)-4-(2-((( 1 R*3*--2 methoxyacetamido)cyclohexyl)methy)-2H-tetrazol-5-yi)-6 methylpicolinamide 243 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 R*,3R*)-3 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 244 rac-2-(( I 3*--(5(-(-ehoyezlcabmy)6 methylpyridin-4-yI)-2H-tetrazo-2-yl)methyl)cyclohexylamfilo)-2 oxoethyl acetate 245 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 R*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yY)-6 methyipicolinamide 246 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 R*,3R*)-3-(3 methoxypropanamido)cyclohexyl)methyl).2H-tetrazol-5-y )-6 methyipicolinamide 247 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 R*,3R*)-3-(2 aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yi )-6 methylpicolinamide 248 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((( 1 R*,3R*)-3 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yr~picolinamide 249 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 S*,3R*)3aminocyclopentyl)methyl ) 2 H-tetrazol-5-yl)-6-m ethyl picoi inam id e 250 rac-N-(3-Methoxybenzyl)-6-methy-4-(2-(((1 S*,3R*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5 yi)picolinamide 251 rac-N-(3-Methoxybenzyi)-4-(2-(((1 S*,3R*)-3 (ethylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl )-6 methylpicolinamide 252 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 S*,3R*)-3 acetamidocyclopentyl )methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 253 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclopenty)methyl)-2H-tetrazol-5-yi)-6 methylpicolinamide 39 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 254 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(3 hydroxypropanamido)cyclopentyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 255 (trans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyridn-4 yI )-2 H-tetrazol-2- yI)methyl)cyclohexanecarboxyl ate 256 (trans)-4-((5-(2-((4-Fluorobenzyl)carbamoyl)-6-methylpyridin-4-y)-2H tetrazol-2- ylmethyl)cycohexanecarboxylic acid 257 N-(4-Fluorobenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylcarbamoyl)cyclohexyl)methyl)-2H-tetrazol-5 yI)picolinamide 258 N-(4 -F luorobenzyi)-4- (2-(((trans)-4 -(2 -hyd roxyacety)cyclohexyl)m ethyl) 2H-tetrazol-5-yI)-6-methylpicolinamide 259 (trans)-Methyl 4-((5-(2-((3-(hydroxymethyI)benzyl~carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cycloh exanecarboxyi ate 260 (trans)-4-((5-(2-((3-(Hydroxymethyl)benzyl)carbamoyl)-6-methylpyridil 4-yI)-2H-tetrazol-2-yi)methyl)cyciohexanecarboxylic acid 261 (trans)-Methyl 4-((5-(2 -((3-hyd roxybe nzyi)ca rbam oyl)-6-m ethyl pyrid in-4 yl)-2 H-tetrazol-2- yI)m eth yi)cyciohexanecarboxyi ate 262 (trans)-4-((5-(2-((3-Hydroxybenzyl )carbamoyl)-6-methylpyridin-4-y )-2H tetrazol-2-yI)methyl)cyclohexanecarboxyic acid 263 (trans)-Methyl 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6 m ethylipyrid in-4 -yl)-2H-tetrazol -2 yl)meth yl)cycloh exaneca rboxyi ate 264 (trans)-4-((5-(2-((3-(3-Methoxypropoxy)benzyi)carbamoyl)-6 methylpyridin-4-yI)-2H-tetrazol-2-y) methyl)cyclohexanecarboxylic acid 265 (trans)-Methyl 4-((5-(2-((3 ,4-difluorobenzyl )carbamoyl)-6-methylpyridin 4 -yI)-2 H-tetra zoi -2- y)methyl)cyclohexanecarboxyl ate 266 (trans)-4-((5-(2-((3,4-Difluorobenzyl)carbamoyl)-6-methylpyridin-4-y) 2 H-tetrazol-2-yl )methyl)cyclohexaner-arboxylic acid 267 (trans)-Methyl 4-((5-(2-((3-methoxybenzyi )carbamoyl)-6-methylpyridin-4 yi )-2 H-tetrazol-2-yl)meth yl)cycl oh exaneca rboxyl ate 268 (trans)-4-(( 5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yi)-2H tetrazoi-2-yI)methyl)cyclohexanecarboxylic acid 269 N-(3-Methoxybenzyl)-6-methyi-4-(2-(((trans)-4-(piperidine- 1 carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide 270 4-(2-(((trans)-4-((2-Methoxyethyl)carbamoyl)cyclohexyl )methyl)-2H tetrazol-5-yl)-N-(3-methoxybenzy )-6-methylpicolinamide 271 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(morpholine-4 carbonyl)cyclohexyl)methyl )-2H-tetrazol-5-yI)picolinamide 272 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (dimethylcarbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yI)-6 methylpicolinamide 273 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (isopropylcarbamoyl)cyciohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 274 4-(2-(((trans)-4-((2-Amino-2-oxoethyl)carbamoyl )cyclohexyl)methyl)-2H tetrazol-5-yI)-N-(3-methoxybenzyl )-6-methylpicoiinamide 40 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 275 N-(3-MethoxybenzyI)-6-methyI-4-(2-(((trans)-4 (methylcarbamoyl )cyclohexyl )methyl)-2H-tetrazol- 5 yl)picolinamide 276 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (ethylcarbamoyl)cyclohexyl )methyl)-2H-tetrazol-5-yl )-6 methylpicolinamide 277 4-(2-(((trans)-4-((2-Hydroxyethyl)carbamoyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-N-(3-methoxybenzyl)-6-methylpicolinamide 278 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H tetrazol-5-yJ)-6-methylpicolinamide 279 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methy)-2H tetrazoi-5-yl )-6-methylpicolinamide 280 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2 hydroxyacetyl )cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 281 (trans)-Methyl 4-((5-(2-((3-(Difluoromethoxy)benzyl)carbamoyl)-6 methylpyridin-4-yl )-2H-tetrazol-2 yi)methyl)cyclohexanecarboxylate 282 (trans)-4 -((5-(2-((3-(Difluorom ethoxy)benzyi)carbamoyl)-6-m ethyp yri din 4-yl)-2H-tetrazol-2-yl)methyl)cyciohexanecarboxylic acid 283 N-(3-(Difluoromethoxy)benzyl )-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 284 (trans)-Methyl 4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6 mnethyl pyrid in -4-yI)-2 H-tetrazol -2 yl)meth yl)cyc lohexanecarboxyl ate 285 (trans)-4-((5-(2 -((4-Fl uoro- 3-methyl ben zyl)carbamoyl)-6-m ethyl pyrid in-4 yI)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid 286 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4 carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 287 N-(4 -F luoro-3-m ethyl benzyl )-4-(2 -(((trans)-4-cya nocyclohexyl )meth yl ) 2H-tetrazol-5-yl)-6-methylpicolinamide 288 (trans)-Methyl 4-((5-(2-((3-Ethylbenzyl)carbamoyI)-6-methylpyridin-4-yl) 2H-tetrazol-2-yI)methyl)cyclohexanecarboxylate 289 (trans)-4-((5-(2-((3-Ethyibenzyl)carbamoyl)-6-methylpyridifl-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylic acid 290 N-(3- Ethyl ben zyl)-4-(2 -(((trans)-4 -carbamoycyclohexyl)m eth yl)-2 H tetrazol-5-yl)-6-methyipicolinamide 291 (trans)-Methyl 4-((5-(2-((3-Cya nobenzyl)carbam oyl)-6-m ethyl pyrid in-4 yl )-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate 292 (trans)-4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyridil-4-y)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylic acid 293 (trans)-Methyl 4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyridin-4 yI)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate 294 (trans)-4-((5-(2 -((3- Ethoxyben zyl)carba moyl)-6-m ethyl pyrid i-4 -yl)-2 H tetrazol-2-yI)methyl)cyclohexanecarboxylic acid 295 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl )methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 41 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 296 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H tetra zol- 5-yl)-6-m ethyl picol ina mide 297 (trans)-Methyl 4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazoi-2 yI )meth yl)cycloh exanecarboxyl ate 298 (trans)-4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yI)methyl)cyclohexanecarboxylic acid 299 N-(4-Fluoro-3-methoxybenzyl )-4-(2-(((trans)-4 carbamoylcyclohexyl )methyl )-2H-tetrazol-5-yl)-6 m ethyl picol inam ide 300 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl )methyl ) 2H-tetrazol-5-yI)-6-methylpicolinamide 301 (trans)-Methyl 4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazo1-2 yl )methyl)cyclohexanecarboxylate 302 (trans)-4-((5-(2-((3-Chioro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4 yl )-2H-tetrazol-2-yt)methyl)cyclohexanecarboxylic acid 303 N-(3-Chloro-4-fluorobenzyi)-4-(2-(((trans)-4 carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yI)-6 m ethyl picol inam ide 304 N-(3-Ghloro-4-fluorobenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl) 2H-tetrazol-5-yI)-6-methylpicolinamide 305 (trans)-Methyi 4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)carbamoyl) 6-methylpyridin-4-yI)-2H-tetrazol-2 yI )m ethyl)cycloh exanecarboxyl ate 306 (trans)-4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2 yi)methyl)cyclohexanecarboxylic acid 307 N-((2,3-Dihydrobenzofuran-5-yl)methyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 308 N-(3-(rrifluoromethyr)benzyt)-4-(2-(((trans)-4 (hydroxyrnethyl)cyclohexyl)methyl)-2H-tetrazol-5-y )-6 methylpicolinamide 309 N-(3-(Trifluoromethoxy)benzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 310 N-(3-Chlorobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 311 N-(3-Methylbenzyl)-4-(2-(((trans)-4-(hydroxymethyl )cyclohexyl)methyl ) 2H-tetrazol-5-yI)-6-methylpicolinamide 312 N-(3- Ethyl ben zyl)-4-(2-(((trans)-4 -(h ydroxymeth yl)cycloh exyl )meth yl) 2H-tetrazol-5-yI)-6-methylpicolinamide 313 N-(3-lsopropoxybenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 314 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexylmethyl) 2H-tetrazoi-5-yl)-6-methylpicolinamide 42 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 315 N-(3,4-Difluorobenzyr)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 316 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 317 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 318 N-(3-(Hydroxymethyl)benzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yI)-6 methylpicolinamide 319 N-(3-Hydroxybenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 320 N-(3-Fluoro-5-methoxybenzyl)-4-(2-(((trans)-4 (hydroxymethyi)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 321 N-((2,3-Dihydrobenzofuran-6-yl)methyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 322 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 323 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 324 N-(3-Bromobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl) 2H-tetrazol-5-yi)-6-methylpicolinamide 325 N-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 326 N-(3-Propoxybenzyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 327 N-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 328 4-(2-(((trans)-4-(Hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-N ((2-methoxypyridin-4-yl)methyl)-6-methylpicolinamide 329 N-(4-Fluorobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 330 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(hydroxymethyl)cyclohexyl)methyl) 2H-tetrazol-5-yi)-6-methylpicolinamide 331 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxypropan-2 yl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 332 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxypropan-2 yl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 333 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-hydroxycyclohexy)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 43 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 334 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 335 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 336 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 337 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 338 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 339 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 340 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 341 rac-N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3 oxocyclopentyl)methyl)-2H-tetrazol-5-yl)picolinamide 342 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3R*)-3 hydroxycyclopentyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 343 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3S*)-3 hydroxycyclopentyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 344 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-hydroxy-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 345 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-hydroxy-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 346 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 347 N-(3-Hydroxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 348 N-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 349 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide 350 N-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazo-5 yl)picolinamide 351 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 352 N-(3-Methoxybenzyl)-4-(2-(((trans)-4 (acetamidomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 44 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 353 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamidomethyl)cyclohexyl )methyl)-2H-tetrazol-5 yl)picolinamide 354 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 (aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 355 rac-N-(3-Methoxybenzyl)-4-(2-((( 1R*,3S*)-3 (hydroxymethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 356 rac-N-(3-Methoxybenzyl)-4-(2-((( 1 R*,3S*)-3 (aminomethyl )cyclopentyl )methyl )-2H-tetrazol-5-yl )-6 methylpicolinamide 357 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((( 1 R*,3S*)-3 (methylsulfonamidomethyl)cyclopentyl)methyl)-2H-tetrazol-5 yl)picolinamide 358 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H tetrazol-5-yl)picolinamide 359 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)- 1 -(methylsulfonyl )piperidin-3 yl )methyl)-2H-tetrazol-5-yl)picolinamide 360 N-(3-Methoxybenzyl)-4-(2-(((S)-1 -acetylpiperidin-3-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 361 N-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H tetrazol-5-yl)picolinamide 362 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)piperidin-3 yl)methyl)-2H-tetrazol-5-yl)picolinamide 363 N-(3-Methoxybenzyl)-4-(2-(((R)- 1 -acetylpiperidin-3-yl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide 364 N- (4 -Fluoro-3-methoxyben zyl )-6-m ethyl -4 -(2- ((S)-p iperid in- 3-ylmnethyl ) 2H-tetrazol-5-yl)picoiinamide 365 N-(4-Fluoro-3-methoxybenzyl)-6-methyi-4-(2-(((R)- 1 (methylsulfonyl)piperidin-3-yl)methyl)-2H-tetrazol-5 yI )picolinamide 366 N-(4-Fluoro-3-methoxybenzyl )4-(2-(((S)- 1 -acetylpiperidin-3-yl)methyl) 2 H-tetrazol-5-yi)-6-m ethyl picol inam ide 367 N-(4-Fluoro-3-methoxybenzyl )-6-methyl-4-(2-((R)-piperidin-3-ylmethyl) 2H-tetrazol-5-yl)picolinamide 368 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-I (methylsulfonyl )piperidin-3-yl )methyl)-2H-tetrazol-5 yl)picolinamide 369 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1 -acetylpiperidin-3-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 370 N-(4 -FlIu oro- 3-methoxyben zyl )-6-m ethyl -4 -(2-((R)-pyrrol id in-3-ylm eth yl) 2H-tetrazol-5-yl)picolinamide 371 N-(4-Fiuoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)- 1 (methylsulfonyl )pyrrolidin-3-yI)methyl)-2H-tetrazol-5 yi)picolinamide 372 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)- 1 -acetylpyrroliclin -3-yl)m ethyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 373 2-((R)-3-((5-(2-((4-Fluoro-3-methoxybenzyl )carbamoyl)-6-methylpyridin 4-yI)-2H-tetrazol-2-yf)methyl)pyrrolidin- 1-yQ)-2-oxoethyI acetate 45 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 374 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1-(2-hydroxyacetyl)pyrrolidin-3 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 375 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-((1 -benzyl-5-oxopyrrolidin-3 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 376 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-((1 (methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide 377 N-(3-Ethoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4 yl)methyl)-2H-tetrazol-5-yl)picolinamide 378 N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin 4-yl)methyl)-2H-tetrazol-5-yI)picolinamide 379 N-(3-Methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5 yl)picolinamide 380 N-(3-Methoxybenzyl)-4-(2-((1-(2-hydroxy-2-methylpropanoyl)piperidin-4 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 381 N-(3-Methoxybenzyl)-4-(2-((1-(3-aminopropanoyl)piperidin-4-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 382 N-(3-Methoxybenzyl)-4-(2-((1-(2-aminoacetyl)piperidin-4-yl)methyl)-2H tetrazo-5-yl)-6-methylpicolinamide 383 N-(3-Methoxybenzyl)-4-(2-((1 -acetylpiperidin-4-yl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 384 N-(3-Methoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4 yl)methyl)-2H-tetrazol-5-yl)picolinamide 385 N-(3-Methoxybenzyl)-4-(2-((1 -isobutyrylpiperidin-4-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 386 N-(3-Methoxybenzyl)-6-methyl-4-(2-((1 -(methylcarbamoyl)piperidin-4 yl)methyl)-2H-tetrazol-5-yl)picolinamide 387 N-(3-Chloro-4-fluorobenzyl)-6-methy)-4-(2-(piperidin-4-ylmethyl)-2H tetrazol-5-yl)picolinamide 388 N-(3-Chloro-4-fluoroben zyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin 4-yl)methy))-2H-tetrazol-5-y))pico)inamide 389 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-methyl-4-(2-(piperidin-4 ylmethyl)-2H-tetrazol-5-yl)picolinamide 390 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-methyl-4-(2-((1 (methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide 391 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H tetrazol-5-yl)picolinamide 392 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((1 (methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide 393 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-morpholin-2-ylmethyl) 2H-tetrazol-5-yl)picolinamide 394 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-4-acetylmorpholin-2-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 395 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2-ylmethyl) 2H-tetrazol-5-yl)picolinamide 396 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)-4-acetylmorpholin-2-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide 46 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 397 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((R)-4 (methylsulfonyl)morpholin-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide 398 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2-ylmethyl)-2H tetrazol-5-yl)picolinamide 399 N-(3-Methoxybenzyl)-4-(2-(((S)-4-acetylmorpholin-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 400 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)-4-(methylsulfonyl)morpholin-2 yl)methyl)-2H-tetrazol-5-yl)picolinamide 401 rac-4-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3 methoxybenzyl)-6-methylpicolinamide 402 rac-4-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-y)-N-(4-fluoro-3 methylbenzyl)-6-methylpicolinamide 403 rac-N-(3-Methoxybenzyl)4-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan 2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 404 N-(3-Methoxybenzyl)-4-(2-(((2S,5R)-5-(hydroxymethyl)- 1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 405 N-(3-Methoxybenzyl)-4-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 406 rac-(2S*,5S*)-Methyl 5-((5-(2-((3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2 carboxylate 407 rac-(2S*,5S*)-5-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4 yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylic acid 408 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hydroxypropan-2-yl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 409 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 410 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 411 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5R*)-5-cyano-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 412 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 413 rac-(2S*,5S*)-Methyl 5-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2 carboxylate 414 rac-(2S*,5S*)-5-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2 carboxylic acid 415 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hydroxypropan 2-yl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 416 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 417 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano-1,4-dioxan 2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 418 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-cyano-1,4-dioxan 2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 47 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 419 ra--4Fur--ehxbny)-2((SS)5(-yrxaey) 1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicoiinamide 420 rac-(2S*,5S)-MethyI 5-((5-(2-((3-chloro-4-fluorobenzyl )carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazo1-2-yl)methyl)- 1 ,4-dioxane-2 carboxylate 421 rac-(2S*,5S'*)-5-((5-(2-((3-Chloro-4-fluorobenzyI)carbamoyl)-6 methylpyridin-4-yI)-2H-tetrazol-2-yl)methyl )- 1 ,4-dioxane-2 carboxylic acid 422 rac-N-(3-Methoxybenzyl )4-(2-(((2R*, 5S*)-5-(aminomethyl)- 1,4-dioxan 2-yi)methyi)-2H-tetrazol-5-yl)-6-methylicolinamide 423 ra--3Mtoyezl 6mty--2((R,5S*)-5 (methylsulfonamidomethyl)- 1,4-dioxan-2-yl)methyl)-2H-tetrazol 5-yi)picolinamide 424 ra--3Mtoyezl4(-(( ,S)5(ctmdmty)1,4 dioxan-2-yi)methyl)-2H-tetrazo-5-y )-6-methylpicolinamide 425 N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydrofuran-2-yl)methyl)-2H tetrazol-5-yl)picolinamide 426 N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-4 yl)methyl)-2H-tetrazol-5-yl)picolinamide 427 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-yI)picolinamide 428 (-)-N- (3-Methoxybenzyl)-6-m ethyli-4-(2-((tetrah yd ro-2H-pyran-2 yi)methyl)-2H-tetrazol-5-yl)picolinamide 429 ()N-(3-Methoxybenzyl)-6-m ethyl -4 -(2- ((tetrahydro-2H-pyran -2 yl)methyl)-2H-tetrazol-5-yI)picolinamide 430 rac-N- (4 -FlIuoro-3-methoxybenzyl)-6-m ethyl-4 -(2- ((tetra hyd ro-2 H-p yran 2-yi)methyl)-2H-tetrazol-5-yI)picolinamide 431 rac -N- (4 -Flu oro-3 -m ethylbenzyl)-6-methyl-4-(2-((tetrahydro-2 H- pyran-2 yl)methyl)-2H-tetrazol-5-yl)picolinamide 432 rac-N-(4-Fluoro-3-methoxybenzyl )-6-methyl-4-(2-((tetrahydro-2H-pyran 3-yt)methyl)-2H-tetrazol-5-yl )picolinamide 433 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-3 yl)methyl)-2H-tetrazoi-5-yI)picolinamide 434 ra--4Fur-3mtoyezl)4(-(2*5R*)-5-hydroxy tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 435 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(( 1 S*,2S*,4R*)-7-oxa bicyclo[2.2. 1ljheptan-2-ylmethyl)-2H-tetrazol-5-y)-6 methylpicolinamide 436 Ethyl 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazoi -2-yl)methyl)bicyclo[2.2.2loctan e- 1 -carboxyl ate 437 4 -((5-(2(+3 -Methoxyben zyl )carbamoyl)-6-m ethyl pyrid in-4-yl)-2H tetrazol-2-yl)methyl)bicyclo[2.2 .2]octane-l1-carboxylic acid 438 N-(3-Methoxybenzyl)-4-(2-((4-(hydroxymethyl)bicyclo[2 .2.2joctan-1 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 439 4-(2-((4-(Hydroxymethyl)pentacyclo[4 .2 .0.0 2
,
5 .01.1.01.
7 ]oct- 1 -yl)methyi) 2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-6-methylpyridine-2 carboxamide 440 4-((5-(2-(( 3-Methoxybenzyl)amino)carbonyl)-6-methylpyridin-4-yl)-2H tetra zol -2 -yl)meth y)cu ban e- 1 -carboxylic acid 48 WO 2009/016498 PCT/1B2008/002046 Table 3 Example Compound Name N 0. 441 4-(2-((4-(Aminocarbonyl)pentacyclo4.2 .00 2 5 .0 3 8 .0 47 ljoCt- 1 -yI)methyl) 2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-6-methylpyridine-2 carboxamide 442 4-(2-((4-Cyanopentacyclo(4 .2 .0.02. .0 .,,0 47joct- Il-yI)methyl)-2H-tetrazol 5-yI )-N-(3-methoxybenzyl)-6-methylpyridine-2-carboxam ide 443 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-3-methylbutan-2-y)-2H tetrazol-5-yi)picolinamide 444 N-(4-Fluoro-3-methoxybenzyl)-4-(2-((R)-3-hydroxy-2-methylpropyl)-2H tetrazol -5- yI)-6-m ethyl picol inam ide 445 N-(4-Fluoro-3-methoxybenzyl)-4-(2-((S)-3-hydroxy-2-methylpropyl)-2H tetrazot-5-yi)-6-methylpicolinamide 446 N-(4-Fluoro-3-methylbenzyl )-4-(2-isobutyl-2H-tetrazol-5-y)-6 methylpicolinamide 447 N-(4-Fluoro-3-methoxybenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)-6 methylpicolinamide 448 N-(3-Methoxybenzyl)-4-(2-isobutyl-2H-tetrazol-5-y)-6 methylpicolinamide 449 6-((4- (2-I1sobu tyl-2H-tetrazol -5-yl)-2-m ethyl picol inam id o)meth yl)- 1 H ndole-2-carboxamicle 450 N-(3-methoxybenzyl)-4-( 1 -(((trans)-4-aminocyclohexyl)methyl)- I H- 1,2,4 triazol-3-yl)-6-methylpicolinamide 451 N-(3-MethoxybenzyI)-6-methyl-4-(I -(((trans)-4 (m eth ylsulIfonam ido)cyclohexyl)m ethyl)- 1 H-i ,2,4-triazol-3 yI)picolinamide 452 N-(3-Methoxybenzyl)-4-( 1 -(((trans)-4-acetamidocyclohexyl)methyl)- I H 1 ,2,4-triazol-3-yi)-6-methyipicoiinamide 453 2-((trans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-y ) 1 H- 1,2 ,4-triazol- 1 -yI)methyl )cyclohexylamino)-2-oxoethyI acetate 454 N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyi)-1 H-i ,2,4-triazol-3-yI)-6 methylpicolinamidle 455 N-(4-Fluoro-3-methoxybenzyl)-4-( 1 -(((trans)-4-aminocyclohexyl)methyl) 1 H-i ,2,4-triazol-3-yl)-6-methylpicolinamide 456 N-(4-Fiuoro-3-methoxybenzyl)-6-methyl-4-( 1 -(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-1 H- 1,2 ,4-triazol-3 yi)picolinamide 457 N-(4-Fluoro-3-methoxybenzyl)-4-( 1 -(((trans)-4 acetamidocyclohexyl)methyl)- 1 H- 1,2 ,4-triazol-3-yI)-6 methylpicolinamidle 458 2-((trans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yI)- 1 H- 1,2 4-triazol- 1 yl)methyl)cyclohexylamino)-2-oxoethy acetate 459 N-(4-Fluoro-3-methoxybenzyl )-4-( 1 -(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyl)- I H-i ,2,4-triazol-3-yI)-6 m ethyl picol inam ide 460 N- (4- Fl uoro-3-m ethyl benzyl )-4-( 1 -(((trans)-4-aminocyclohexyl)methyl) 1 H-i ,2,4-triazol-3-yl)-6-methylpicolinamide 49 WO 2009/016498 PCT/IB2008/002046 Table 3 Example Compound Name N 0. 461 N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1 -(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3 yl)picolinamide 462 N-(4-Fluoro-3-methylbenzyl)-4-(1 -(((trans)-4 acetamidocyclohexyl)methyl)- 1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide 463 2-((trans)-4-((3-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6 methylpyridin-4-yl)-1 H- 1,2,4-triazol- 1 yl)methyl)cyclohexylamino)-2-oxoethy acetate 464 N-(4-Fluoro-3-methylbenzyl)-4-(1 -(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyl)- 1 H-1,2,4-triazol-3-yl)-6 methylpicolinamidemide 465 N-(3-Methoxybenzyl)-4-(1 -(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide 466 rac-N-(3-Methoxybenzyl)-4-(1-(((2S*,5R*)-5-(hydroxymethyl)- 1,4-dioxan 2-yl)methyl)-1 H- 1,2,4-triazol-3-yl)-6-methylpicolinamide 467 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(1-(((2S*,5R*)-5-(hydroxymethyl) 1 ,4-dioxan-2-yl)methyl)- 1 H- 1,2,4-triazol-3-yl)-6 methylpicolinamide 468 rac-N-(4-Fluoro-3-methylbenzyl)-4-(1-(((2S*, 5R*)-5-(hydroxymethyl)- 1,4 dioxan-2-yl)methyl)- 1 H-1,2,4-triazol-3-yl)-6-methylpicolinamide Another embodiment of the invention is a pharmaceutical composition comprising a compound as described hereinabove, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. 5 Another embodiment of the invention is a method for inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal an MMP-13 inhibiting amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating a disease mediated by an MMP 13 enzyme, comprising administering to a patient suffering from such a disease a nontoxic effective 10 amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating arthritis, comprising administering to a patient suffering from an arthritis disease a nontoxic antiarthritic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating osteoarthritis, comprising 15 administering to a patient suffering from osteoarthritis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating rheumatoid arthritis, comprising administering to a patient suffering from rheumatoid arthritis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. 50 WO 2009/016498 PCT/IB2008/002046 Another embodiment of the invention is a method for treating psoriatic arthritis, comprising administering to a patient suffering from psoriatic arthritis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating a cancer, comprising 5 administering to a patient suffering from a cancer a nontoxic anti-cancer effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating inflammation, comprising administering to a patient suffering from inflammation a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. 10 Another embodiment of the invention is a method for treating chronic obstructive pulmonary disease, comprising administering to a patient suffering from chronic obstructive pulmonary disease a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating psoriasis, comprising 15 administering to a patient suffering from psoriasis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention is a method for treating asthma, comprising administering to a patient suffering from asthma a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. 20 Another embodiment of the invention is a method for treating inflammatory bowel disease, comprising administering to a patient suffering from inflammatory bowel disease a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof. For the purposes of this invention, the term "arthritis", which is synonymous with the phrase 'arthritic condition", includes osteoarthritis, rheumatoid arthritis, degenerative joint disease, 25 spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and psoriatic arthritis. An allosteric inhibitor of MMP-13 having an anti-arthritic effect is a compound as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the arthritic diseases and disorders listed above. As used herein, the term "alkyl" refers to a straight or branched chain monovalent hydrocarbon 30 radical. For example, a C 1 .6 alkyl radical is a straight or branched chain monovalent hydrocarbon radical having I to 6 carbon atoms. Examples of C .6 alkyl radicals include methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, and 1-hexyl. As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical. For example, a C1.6 alkylene radical is a straight or branched chain divalent hydrocarbon 35 radical having 1 to 6 carbon atoms. Examples of C1.6 alkylene radicals include methylene, ethylene, 1 propylene, 2-propylene, 1 -butylene, 2-butylene, 2,2-dimethylethylene, 1 -pentylene, 2-pentylene, 2,2 dimethylpropylene, and 1-hexylene. As used herein, the term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical. For example, a C3-6 cycloalkyl radical is a cyclic monovalent hydrocarbon radical having 1 to 6 carbon 51 WO 2009/016498 PCT/IB2008/002046 atoms. Examples of Cm cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "IC50" means the concentration of a compound, usually expressed as pM or nM, required to inhibit an enzyme's catalytic activity by 50%. 5 As used herein, the phrase "cartilage damage" means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface. The phrase "treating", which is related to the terms "treat" and "treated", means administration of an invention combination as defined above that inhibits the progress, prevents further progress, or 10 reverses progression, in part or in whole, of any one or more symptoms of any one of the diseases and disorders listed above. The phrase "invention compound" means a compound of Formula 1, or a pharmaceutically acceptable salt thereof, as fully defined above. The term "NSAID" is an acronym for the phrase "nonsteroidal anti-inflammatory drug", which 15 means any compound which inhibits cyclooxygenase-1 ("COX-1") and cyclooxygenase-2. Most NSAIDs fall within one of the following five structural classes: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal; and (5) oxicams, such as 20 piroxim, peroxicam, sudoxicam, and isoxicam. Other useful NSAIDs include aspirin, acetominophen, indomethacin, and phenylbutazone. Selective inhibitors of cyclooxygenase-2 as described above may be considered to be NSAIDs also. A selective inhibitor of COX-2 is a compound that inhibits COX-2 selectively versus COX-1 such that a ratio of IC50 for a compound with COX-1 divided by a ratio of ICso for the compound with 25 COX-2 is greater than, or equal to, 5, where the ratios are determined in one or more assays. All that is required to determine whether a compound is a selective COX-2 inhibitor is to assay a compound in one of a number of well know assays in the art. The term "drugs", which is synonymous with the phrases "active components", "active compounds", and "active ingredients", includes celecoxib, or a pharmaceutically acceptable salt 30 thereof, valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric inhibitor of MMP 13, and may further include one or two of the other therapeutic agents described above. An allosteric inhibitor of MMP-1 3 is any compound of Formula I that binds allosterically into the S1' site of the MMP-1 3 enzyme, including the Si' channel, and/or the S1" site, without ligating, coordinating, or binding the catalytic zinc of the MMP-13. 35 Certain of the invention compounds possess one or more chiral centers, and each center may exist in the R or S configuration. The scope of the present invention encompasses any diastereomeric, enantiomeric, or epimeric form of invention compound, as well as mixtures thereof. Compounds of Formula I may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures. Methods to obtain preferentially a single enantiomer from a mixture of 40 individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of 52 WO 2009/016498 PCT/IB2008/002046 organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non racemic reagent followed by separation of the resulting diastereomers by common methods (e.g. crystallization, chromatographic separation, or distillation) and chemical reversion to scalemic 5 compound, Simulated Moving Bed technology, or high/medium-pressure liquid chromatography employing a chiral stationary phase These techniques may be performed on the final compounds of Formula I or on any intermediates to compounds of Formula I which bear a stereogenic center. Also, to facilitate separation by any of the methods described above, the compounds of Formula I or any intermediates to the compounds of Formula I which bear a stereogenic center may be transiently 10 reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques. Additionally, certain invention compounds may exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers of 1,2-disubstituted alkenyl groups or cis and trans isomers of disubstituted cyclic groups. Any cis, trans, syn, anti, entgegen (E), or zusammen (Z) isomer of a 15 compound of Formula 1, as well as mixtures thereof, is encompassed within the scope of the present invention. Certain invention compounds can exist as two or more tautomeric forms. Tautomeric forms of the invention compounds may interchange, for example, via enolization/de-enolization, 1,2-hydride, 1,3-hydride, or 1,4-hydride shifts, and the like. Any tautomeric form of a compound of Formula 1, as 20 well as mixtures thereof, is encompassed within the scope of the present invention. Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present invention. Encompassed within the scope of the present invention are isotopically-labelled compounds of 25 Formula 1, which are identical to those recited above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F and 36C1, respectively. Compounds 30 of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for 35 their ease of preparation and delectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of those described above in this invention can generally be prepared by carrying out the procedures incorporated by reference above 53 WO 2009/016498 PCT/IB2008/002046 or disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. Some of the invention compounds are capable of further forming nontoxic pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts. The acid addition salts 5 are formed from basic invention compounds, whereas the base addition salts are formed from acidic invention compounds. All of these forms are within the scope of-the compounds useful in the invention. Pharmaceutically acceptable acid addition salts of the basic invention compounds include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, 10 hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, 15 iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate or galacturonate. 20 An acid addition salt of a basic invention compound is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner. The free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner. The free base forms of compounds prepared according to a process of the 25 present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the invention compounds and their respective acid addition salt forms are equivalent for purposes of the present invention. A nontoxic pharmaceutically acceptable base addition salt of an acidic invention compound 30 may be prepared by contacting the free acid form of the compound with a metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na'), potassium cation (K*), magnesium cation (Mg 2 +), calcium cation (Ca 2 +), and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, 35 and procaine. A base addition salt of an acidic invention compound may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner. The free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner. 40 The free acid forms of the invention compounds differ from their respective salt forms somewhat in 54 WO 2009/016498 PCT/IB2008/002046 certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. Certain invention compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms, In general, the solvated forms, including hydrated forms, are equivalent to 5 unsolvated forms and are encompassed within the scope of the present invention. The invention also provides pharmaceutical compositions comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable carrier, diluent, or excipient. The present invention also relates to the formulation of a compound of the present invention 10 alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing; or, in the case of non human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in the feed composition. There is further provided in accordance with the 15 present invention co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination; including co-administration by means of different dosage forms and routes of administration; the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said 20 combination are not being administered to said patient simultaneously. A therapeutically effective amount, or, simply, effective amount, of a compound of Formula I will generally be from about 1 to about 300 mg/kg of subject body weight of the compound of Formula 1, or a pharmaceutically acceptable salt thereof. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight for each component of the combination. In a clinical 25 setting, Fegulatory agencies such as, for example, the Food and Drug Administration ("FDA") in the U.S. may require a particular therapeutically effective amount. In determining what constitutes a nontoxic effective amount or a therapeutically effective amount of a compound of Formula I for treating, preventing, or reversing one or more symptoms of any one of the diseases and disorders described above that are being treated according to the 30 invention methods, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, including the Food and Drug Administration guidelines, or guidelines from an equivalent agency, published clinical studies, the subject's (e.g., mammal's) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by 35 the subject. As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside them, ie, either below or above those ranges, depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller 40 dosages of the compound of Formula I that are less than optimum for a particular subject. Thereafter, 55 WO 2009/016498 PCT/IB2008/002046 the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. Pharmaceutical compositions, described briefly here and more fully below, of an invention 5 combination may be produced by formulating the invention combination in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Alternatively, the compounds of Formula I may be formulated 10 separately. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as 15 peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in 20 relatively small amounts. The compositions can, if desired, also contain other therapeutic agents commonly employed to treat any of the above-listed diseases and disorders. The percentage of the active ingredients of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a total concentration of at least 10% in a solid composition and at 25 least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredients are present, for example, up to about 95%. Preferred routes of administration of a compound of Formula I are oral or parenteral. However, another route of administration may be preferred depending upon the condition being treated. For exampled, topical administration or administration by injection may be preferred for treating conditions 30 localized to the skin or a joint. Administration by transdermal patch may be preferred where, for example, it is desirable to effect sustained dosing. It should be appreciated that the different routes of administration may require different dosages. For example, a useful intravenous ("IV") dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg, of a compound of Formula 1, or a pharmaceutically acceptable salt 35 thereof. The dosage is within the dosing range used in treatment of the above-listed diseases, or as would be determined by the needs of the patient as described by the physician. Compounds of Formula I may be administered in any form. Preferably, administration is in unit dosage form. A unit dosage form of the compound of Formula I to be used in this invention may also comprise other compounds useful in the therapy of diseases described above. A further description of 56 WO 2009/016498 PCT/IB2008/002046 pharmaceutical formulations useful for administering the compounds of Formula I and invention combinations is provided below. The invention also provides combinations, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with another pharmaceutically active component as 5 described herein. The active components of the invention combinations, may be formulated together or separately and may be administered together or separately. The particular formulation and administration regimens used may be tailored to the particular patient and condition being treated by a practitioner of ordinary skill in the medical or pharmaceutical arts. 10 For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel@), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold. The compounds of the invention can also be used in combination with existing therapeutic 15 agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as etoricoxib and rofecoxib, analgesics and intraarticular 20 therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc. The active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor 25 antagonists, IL-1 processing and release inhibitors, ILra, H1 -receptor antagonists; kinin-B1 - and B2 receptor antagonists; prostaglandin inhibitors such as PGD-, PGF- PGI2 - and PGE-receptor antagonists; thromboxane A2 (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC4 , LTD4/LTE4 - and LTB4 -inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine 30 and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid, sulfinpyrazone and benzbromarone. The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis 35 platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate. The compounds of the present invention may also be used in combination with anti hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure and myocardial 40 infarction, selected from vasodilators such as hydralazine, p-adrenergic receptor antagonists such as 57 WO 2009/016498 PCT/IB2008/002046 propranolol, calcium channel blockers such as nifedipine, a2-adrenergic agonists such as clonidine, a adrenergic receptor antagonists such as prazosin and HMG-CoA-reductase inhibitors (anti hypercholesterolemics) such as lovastatin or atorvastatin. The compounds of the present invention may also be administered in combination with one or 5 more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents. The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and 10 inhibitors of neuronal nitric oxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate. The compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin. 15 Compounds of Formula I may be used in combination with a COX-2 selective inhibitor, more preferably celecoxib, valdecoxib, parecoxib, lumiracoxib, or rofecoxib, or with compounds such as etanercept, infliximab, leflunomide, or methotrexate, and the like. Compounds of Formula I may be used in combination with biological therapeutics useful for treating arthritic conditions, including CP-870, etanercept (a tumor necrosis factor alpha ("TNF-alpha") 20 receptor immunoglobulin molecule; trade names ENBREL@ and ENBREL ENTANERCEPT@ by Immunex Corporation, Seattle, Washington), infliximab (an anti-TNF-alpha chimeric IgG 1K monoclonal antibody; tradename REMICADE@ by Centocor, Inc., Malvern, Pennsylvania), methotrexate (tradename RHEUMATREX@ by American Cyanamid Company, Wayne, New Jersey), and adalimumab (a human monoclonal anti-TNF-alpha antibody; tradename HUMIRA@ by Abbott 25 Laboratories, Abbott Park, Illinois). The invention also provides methods of inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal a compound of Formula 1, or a pharmaceutically acceptable salt thereof. The invention also provides methods of treating a disease mediated by an MMP-1 3 enzyme in 30 a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention also provides methods of treating diseases such as heart disease, multiple sclerosis, osteo and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency, inflammatory bowel disease, heart failure, age-related macular degeneration, chronic 35 obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administering to the patient a compound of Formula 1, or a pharmaceutically acceptable salt thereof. Other mammalian diseases and disorders which are treatable by administration of an invention combination alone, or contained in a pharmaceutical composition as defined below, include 40 fever (including rheumatic fever and fever associated with influenza and other viral infections), 58 WO 2009/016498 PCT/IB2008/002046 common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung 5 cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial 10 joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, 15 headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and || diabetes, diabetic retinopathy, 20 neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock), epilepsy, 25 convulsions, and septic shock. One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease. 30 This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a compound of this invention to a mammal, including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above and said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions: 35 A) where a joint has become seriously inflamed as well as infected at the same time by bacteria, fungi, protozoa and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal and/or antiviral therapeutic agents; B) where a multi-fold treatment of pain and inflammation is desired, said inhibitory 40 compound is administered in combination with inhibitors of other mediators of 59 WO 2009/016498 PCT/IB2008/002046 inflammation, comprising one or more members independently selected from the group consisting essentially of: 1. NSAIDs; 2. H 1 -receptor antagonists; 5 3. kinin-B 1 - and B 2 -receptor antagonists; 4. prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PG 2 and PGE-receptor antagonists; 5. thromboxane A 2
(TXA
2 -) inhibitors; 6 5-, 12- and 15-lipoxygenase inhibitors; 10 7. leukotriene LTC 4 -, LTD 4
/LTE
4 - and LTB 4 -inhibitors; 8. PAF-receptor antagonists; 9. gold in the form of an aurothio group together with one or more hydrophilic groups; 10. immunosuppressive agents selected from the group consisting of cyclosporine, 15 azathioprine and methotrexate; 11. anti-inflammatory glucocorticoids; 12. penicillamine; 13. hydroxychloroquine; 14. anti-gout agents including colchicine; xanthine oxidase inhibitors including 20 allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone and benzbromarone; C) where older mammals are being treated for disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory compound is administered in combination with one or more members independently selected from the group 25 consisting essentially of: 1 . cognitive therapeutics to counteract memory loss and impairment; 2. anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure and myocardial infarction, selected from the group 30 consisting of: a. diuretics; b. vasodilators; c. p-adrenergic receptor antagonists; d. angiotensin-Il converting enzyme inhibitors (ACE-inhibitors), alone or 35 optionally together with neutral endopeptidase inhibitors; e. angiotensin il receptor antagonists; f. renin inhibitors; g. calcium channel blockers; h. sympatholytic agents; 40 i. a 2 -adrenergic agonists; 60 WO 2009/016498 PCT/IB2008/002046 j. a-adrenergic receptor antagonists; and k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics); 3. vinca alkaloids selected from: a. vinblastine; and 5 b. vincristine; 4. growth hormone secretagogues; 5. strong analgesics; 6. local and systemic anesthetics; and 7. H 2 -receptor antagonists, proton pump inhibitors and other gastroprotective 10 agents. The invention method is useful in human and veterinary medicines for treating mammals suffering from one or more of the above-listed diseases and disorders. An allosteric inhibitor of MMP-1 3 may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying an alkyne test compound for inhibition of MMP-1 3 as 15 described, for example, in Biological Methods 1 or 2 of International Patent Application Pub. No. WO 04/014366US200400488637179822, the content of which are herein incorporated by reference. Allosteric inhibition of MMP-1 3 may be identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the test invention compound for inhibition of MMP-13 in the presence of an inhibitor to the catalytic zinc of MMP-13 as described, for example, in Biological Methods 3 or 4 of 20 International Patent Application Pub. No. WO 04/014366US200400488637179822, the content of which are herein incorporated by reference. Further, a compound having an anti-inflammatory, an analgesic, anti-arthritic, or a cartilage damage inhibiting effect, or any combination of these effects, may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the compound in any number of well 25 known assays for measuring determining the compound's effects on cartilage and or other joint tissue damage, arthritis, inflammation, or pain. These assays include in vitro assays that utilize cartilage samples and in vivo assays in whole animals that measure cartilage degradation, inhibition of inflammation, or pain alleviation. For example with regard to assaying cartilage damage in vitro, an amount of a compound or 30 control vehicle may be administered with a cartilage-damaging agent to cartilage such as IL-1, and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content, or by biomarkers of type Il collagen degradation such as CTX-Il or TIINE (Sunyer et al., Osteo. Cartilage 12 (2004) (Suppl. B), p. P84). 35 Further, in vivo studies to assay cartilage damage and/or joint degeneration may be performed as follows: an amount of a compound or control vehicle may be administered with a cartilage damaging agent to an animal or may be administered in the absence of cartilage damaging agents, to animals that have surgery-induced or spontaneous OA lesions in the knee. Examples of surgery-induced animal models include the rat medial meniscus tear model or the dog anterior cruciate ligament 40 transaction model. The effects of the compound being assayed in the animals for effects on cartilage 61 WO 2009/016498 PCT/IB2008/002046 integrity and/or joint structure may be evaluated by gross examination or histopathologic examination of the affected joint(s), and respose to compounds further characterized by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content or biomarkers of type il collagen degradation such as CTX-I1 or TIINE in biological fluids such as urine, 5 plasma, serum or synovial fluids. Effect of the compounds may also be assessed by observation of the effects in an acute model on functional limitations of the affected joint. Several methods of identifying a compound with cartilage damage inhibiting properties are described below. The amount to be administered in an assay is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that 10 the particular assay can effectively accommodate. Similarly, compounds having pain-alleviating properties may be identified using any one of a number of in vivo animal models of pain. Still similarly, compounds having anti-inflammatory properties may be identified using any one of a number of in vivo animal models of inflammation. For example, for an example of inflammation 15 models, see United States patent number 6,329,429, which is incorporated herein by reference. Still similarly, compounds having anti-arthritic properties may be identified using any one of a number of in vivo animal models of arthritis. For example, for an example of arthritis models, see also United States patent number 6,329,429. Other embodiments of the present invention are compounds described herein, or a 20 pharmaceutically acceptable salt thereof, that are 10, >20, >50, 100, or 1000 times more potent versus MMP-1 3 than versus at least two of any other MMP enzyme or TACE. Still other aspects of the present invention are compounds of Formula 1, or a pharmaceutically acceptable salt thereof, that are selective inhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, or versus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes. 25 It should be appreciated that selectivity of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, is a multidimensional characteristic that includes the number of other MMP enzymes and TACE over which selectivity for MMP-13 inhibition is present and the degree of selectivity of inhibition of MMP-13 over another particular MMP or TACE, as measured by, for example, the IC50 in pM of the compound for the inhibition of the other MMP enzyme or TACE divided 30 by the IC5o in pM of the compound for the inhibition of MMP-1 3. As discussed above, one aspect of the present invention is novel compounds that are selective inhibitors of the enzyme MMP-13. A selective inhibitor of MMP-13, as used in the present invention, is a compound that is bX more potent in vitro versus MMP-13 than versus at least one other matrix metalloproteinase enzyme such as, for example, MMP-1, MMP-2, MMP-3, MMP-7, MMP 35 8, MMP-9, or MMP-14, or versus TACE. A preferred aspect of the present invention is novel compounds that are selective inhibitors of MMP-13 versus MMP-1. The invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof, which has an IC50 with any MMP enzyme that is less than or equal to 50 pM. Preferred are compounds of Formula 1, or a pharmaceutically acceptable salt thereof, which have an IC50 with a 40 human full-length MMP-1 3 ("hMMP-1 3FL") or a human MMP-1 3 catalytic domain ("hMMP-1 3CD") that 62 WO 2009/016498 PCT/IB2008/002046 is less than or equal to 50 pM. More preferred are compounds of Formula 1, or a pharmaceutically acceptable salt thereof, which have an IC50 with a human full-length MMP-13 ("hMMP-13FL") or a human MMP-13 catalytic domain ("hMMP-13CD") that is less than or equal to 10 pM. Examples of biological methods useful for determining IC5os for compounds with an MMP are described herein. 5 The advantages of using an invention compound in a method of the instant invention include the nontoxic nature of the compounds at and substantially above therapeutically effective doses, their ease of preparation, the fact that the compounds are well-tolerated, and the ease of topical, IV, or oral administration of the drugs. Another important advantage is that the present invention compounds more effectively target 10 a particular disease that is responsive to inhibition of MMP-13 with fewer undesirable side effects than similar compounds that inhibit MMP-13 that are not invention compounds. This is so because the instant invention compounds of Formula 1, or a pharmaceutically acceptable salt thereof, do not directly, or indirectly via a bridging water molecule, ligate, coordinate to, or bind to the catalytic zinc cation of MMP-1 3, but instead bind at a different location from where natural substrate binds to MMP 15 13. The binding requirements of an allosteric MMP-13 binding site are unique to MMP-13, and account for the specificity of the invention compounds for inhibiting MMP-13 over any other MMP enzyme. See J. Chem. Biol., 2005(12), 181-189. Indeed, prior art inhibitors of MMP-13 bind to the catalytic zinc cations of other MMP enzymes as well as to the catalytic zinc cation of MMP-13, and are consequently significantly less selective inhibitors of MMP-1 3 enzyme. 20 The invention compounds which are invention compounds, and pharmaceutically acceptable salts thereof, are thus therapeutically superior to other inhibitors of MMP-13, or even TACE, because of fewer undesirable side effects from inhibition of the other MMP enzymes or TACE. For example, virtually all prior art MMP inhibitors tested clinically to date have exhibited an undesirable side effect known as muscoloskeletal syndrome ("MSS"). MSS is associated with administering an inhibitor of 25 multiple MMP enzymes or an inhibitor of a particular MMP enzyme such as MMP-1. MSS will be significantly reduced in type and severity by administering the invention compound instead of any prior art MMP-13 inhibitor, or a pharmaceutically acceptable salt thereof. The invention compounds are superior to similar compounds that interact with the catalytic zinc cation of the MMP-13 enzyme as discussed above, even if similar compounds show some selectivity for the MMP-13. 30 General Synthetic Procedures Intermediates for the synthesis of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, may be prepared by one of ordinary skill in the art of organic chemistry by adapting various synthetic procedures incorporated by reference above or that are well-known in the art of organic chemistry. These synthetic procedures may be found in the literature. Alternatively, a skilled 35 artisan may find methods useful for preparing the intermediates in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany. 63 WO 2009/016498 PCT/IB2008/002046 Preparations of the invention compounds may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for 5 example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Missouri, BACHEM, BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom. Syntheses of some invention compounds may utilize starting materials, intermediates, or reaction products that contain a reactive functional group. During chemical reactions, a reactive functional group may be protected from reacting by a protecting group that renders the reactive 10 functional group substantially inert to the reaction conditions employed. A protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and then later remove them. Procedures 15 for introducing and removing protecting groups are well known. Thus, for example, protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), P,p,8-trichloroethoxycarbonyl (TCEC), and /-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), 20 para-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, trifluoromethanesulfonyl, and benzyl. Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for 25 example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal. The following schemes are representative of the methods that can be used to prepare 30 compounds of Formula 1. Starting materials may be obtained by procedures described in the schemes, by procedures well known to one of ordinary skill in organic chemistry, and/or may be obtained commercially. The following schemes are representative of the methods that can be used to prepare compounds of Formula 1. Starting materials may be obtained by procedures described in the schemes, 35 by procedures well known to one of ordinary skill in organic chemistry, and/or may be obtained commercially. 64 WO 2009/016498 PCT/IB2008/002046 CHART A H H W.N 0 W.N 0 NN Y Q - NH Y QN-G Al A2 5 Compounds of formula (1) wherein L is a tetrazole (U = N) or triazole (U = CH) may be prepared as described in Chart A, A compound of formula Al is reacted with an alcohol (G-OH) under Mitsunobu coupling conditions (e.g. Ph 3 P, di-terf-butyl azodicarboxylate) wherein G is a group V-Z as described above and in which reactive functional groups may be protected. Alternatively, a compound of formula Al may be reacted with a compound G-X in the presence of a base (e.g. tertiary amine, sodium 10 hydride) wherein X is Cl, Br, I, alkylsulfonate ester, or arylsulfonate ester. The reagents G-OH or G-X are either commercially available or prepared as described below (Charts J - X). The above reaction conditions may afford one or more positional isomers about the five-membered heterocycle including A2 (Chart A), B1, or B2 (Chart B). Determination of the structural isomer formed is readily possible by someone skilled in the art employing NMR techniques (e.g. H1, gHSQC, gHMBC, gHMBC-N15, and 15 1d NOE experiments) or single crystal X-ray analysis. CHART B H H W.N 0 W.N 0 N' G N' N N Y Q \ ,'N N N-U G-U BI B2 20 65 WO 2009/016498 PCT/IB2008/002046 CHART C Cl CI N N Y N Cl Y N OH C1 C2 O O0O 0 N' N' Y N C1 Y N OH C4 C3 ~ 00 0 -O O0O N) N N Y N CN N HN C5 C6 H H N 0 N 0 w w N Y N CN Y N -- NH N 14 C8 C7 5 Compounds of the formula Al employed in Chart A are prepared as described in Charts C - H below. Hydrolysis of 4,6-dichloropyrimidines of the formula C1 under strongly acidic conditions provide compounds of the formula C2 (Henze, H. R. J. Org. Chem. 1952, 17, 1320-1326). Compounds of the formula C1 are commercially available (Y = H and CH 3 ) or may be prepared by literature procedures wherein Y = (CH 2
)
1 .3CH 3 , CH(CH 3
)C
2
H
5 , and CH 2
CH(CH
3
)
2 (Henze, H. R. J. Org. Chem. 1952, 17, 10 1320-1326); Y = CH(CH 3
)
2 (Gershon, H. J. Med. Chem. 1964, 7,808-811); Y = CF 3 (Inoue, S. J. Org. Chem. 1961, 26, 4504-4508); Y = CH 2 F (Elvidge, J. A. J. Chem. Soc., C, 1968, 2188-2198) or by analogous procedures to those described in these references. Carbonylation of compounds C2 with carbon monoxide and an alcohol solvent (e.g. methanol) in the presence of a palladium catalyst provides esters of the formula C3. Subsequent chlorination of esters C3 followed by reaction with 66 WO 2009/016498 PCT/IB2008/002046 tetraethylammonium cyanide provides compounds of the formula C5. The reaction of cyano derivatives with sodium azide in the presence of zinc bromide provides the tetrazoles C6 which subsequently are reacted with a primary amine of the formula W-NH 2 to provide compounds of the formula C7. Alternatively, cyano derivatives C5 may be reacted with the amine W-NH 2 first to provide 5 C8 which subsequently is subjected to tetrazole formation to provide C7. CHART D O 0 Y N 0 D1 H H WN 0 WN 0 D1 : N I N 'I 0
NH
2 Y N Y N 0 0 D2 D3 H .N 0 W D3 0 N N Y N -NH N H D4 10 Compounds of the formula Al employed in Chart A wherein Q is N and U is CH may be prepared as described in Chart D starting from 4,6-dichloropyrimidines of the formula C1 obtained as described above. Carbonylation of compounds C1 with carbon monoxide and an alcohol solvent (e.g. methanol) in the presence of a palladium catalyst provides esters of the formula D1. Treatment of esters D1 with 15 less than two equivalents of a primary amine of the formula W-NH 2 affords amides D2 which are then subsequently reacted with ammonia to provide bis-amides of the formula D3. Condensation of D3 with dimethylformamide dimethylacetal followed by reaction with hydrazine (Mustazza, C. J. Heterocyclic Chem. 2001, 38, 1119-1129) affords triazoles of the formula D4. Alternatively as described in Chart E, triazoles of the formula D4 may be prepared by reacting nitriles of the formula 20 C8 with hydrazine to provide El which is then heated with formic acid. 67 WO 2009/016498 PCT/IB2008/002046 CHART E H W.N 0 C8 N i D4 Y N
NH
2 NH El 5 CHARTF OH Cl OH CI 0 0 Fl F2 CI CI N Y CN Y 't-Bu 0 F4 F3 CI O 0 N N N NH NH NH N=N' N N F5 F6 H W.N 0 YN N 'NH N zN F7 68 WO 2009/016498 PCT/IB2008/002046 Compounds of the formula Al employed in Chart A wherein Q is CH and U is N may be prepared as described in Chart F. Carboxylic acids of the formula F1 are commercially available (Y = H and CH 3 ) or may be prepared by literature procedures wherein Y = CH 2
CH
3 (Tracy, A. H. J. Org. Chem. 1941, 6, 5 70-76); Y = CH 2
CH
2
CH
3 , CH(CH 3
)
2 , C(CH 3
)
3 (Libermann, D. Bull. Soc. Chim. Fr. 1958, 687-694) or by analogous procedures to those described in these references. Compounds F1 may be chlorinated (e.g. POCl 3 , PCI) and then reacted with tert-butylamine to provide compounds of the formula F3. Further oxidation of secondary amides F3 by treatment with POCI 3 affords the corresponding nitrites F4. The reaction of cyano derivatives F4 with sodium azide in the presence of zinc bromide provides 10 the tetrazoles F5. Carbonylation of compounds F5 with carbon monoxide and an alcohol solvent (e.g. methanol) in the presence of a palladium catalyst provides esters of the formula F6 which are subsequently reacted with a primary amine of the formula W-NH 2 to provide compounds of the formula F7. 69 WO 2009/016498 PCT/IB2008/002046 CHART G OH CI N' N OH O O 0 F1 G1 HO 0 CN OH O O 0 G3 G2 H
C
6
F
5 0 0 .N 0 W N N
C
6
F
5
NH
2 O 0 G4 G5 H H W.N 0 W.N 0 NNN Y NH Y CN N N G7 G6 5 Alternatively, compounds of the formula Al employed in Chart A wherein 0 is CH and U is N may be prepared as described in Chart G starting from compounds F1 obtained as described above. Compounds F1 may be chlorinated (e.g. POCl 3 , PCIs) and then reacted with an alkanol (e.g. methanol) to provide compounds of the formula G1. Cyanation of G1 in the presence of a palladium catalyst affords G2 which is subsequently hydrolyzed under basic conditions (e.g. potassium 10 hydroxide) to provide carboxylic acids of the formula G3. Esterification of carboxylic acids G3 with pentafluorophenyl trifluoroacetate affords diesters of the formula G4. The sequential addition of a primary amine of the formula W-NH 2 followed by ammonia provides amides G5. Dehydration of the primary amide by treatment with POCl 3 affords the corresponding nitrites G6 which react with sodium 70 WO 2009/016498 PCT/IB2008/002046 azide to provide tetrazoles of the formula G7. Intermediates of the formula G5 may also be transformed to triazole derivatives useful in Chart A wherein Q is CH and U is CH as described in Chart H. Condensation of primary carboxamides G5 with dimethylformamide dimethylacetal followed by reaction with hydrazine (Mustazza, C. J. Heterocyclic Chem. 2001, 38, 1119-1129) affords triazoles 5 of the formula H1. CHART H H .N 0 W G5 : N N, NH N zI H1 10 CHART I 1-1 0 111 0 N N Y 'NH N-G N N Nz:1 11 12 H W.N 0 N 13 15 As described in Chart I, compounds of formula 13 may be prepared by reacting a compound of formula 11 (prepared as described in Chart C or Chart F) with an alcohol (G-OH) under Mitsunobu coupling conditions (e.g. Ph 3 P, di-tert-butyl azodicarboxylate) to provide 12 wherein G is a group V-Z as described above and in which reactive functional groups may be protected. Alternatively, a compound of formula 11 may be reacted with a compound G-X in the presence of a base (e.g. tertiary amine, 20 sodium hydride) wherein X is Cl, Br, I, alkylsulfonate ester, or arylsulfonate ester. The reagents G-OH or G-X are either commercially available or prepared as described below (Charts J - X). The resulting ester is then reacted with a primary amine of the formula W-NH 2 to provide compounds of the formula 13. 71 WO 2009/016498 PCT/IB2008/002046 CHART J 0 O O -1 O>=O HO N TsO N O 0 J1 J2 5 CHARTK O OH O OTs 0 0 KI KI CHART L 10 OH OH O 0 0 0 HO- TsO- L1 L2 The reagents G-X employed in Chart A and Chart I above wherein X is an alkylsulfonate ester or arylsulfonate ester are prepared by reaction of an alcohol G-OH with and alkyl- or arylsulfonyl chloride 15 in the presence of a base (e.g. triethylamine or pyridine). Representative examples are shown in Charts J - L wherein the alcohol G-OH may be prepared by literature procedures, e.g. J1, tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate and tert-butyl (S)-2-(hydroxymethyl)morpholine-4 carboxylate (Yanagisawa, H. Heterocycles, 1993, 35, 105-109); K1, (R)-(1,4-dioxan-2-yl)methanol and (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y. Bioorg. Med. Chem. Lett. 2005, 15, 3207-3211). Tosylation 20 of trans-2,5-bis-(hydroxymethyl)-1,4-dioxane (L1) (Summerbell, R. K. J. Am. Chem. Soc. 1954, 76, 6401-6407) affords rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methy 4 methylbenzenesulfonate (L2) which upon resolution by chiral supercritical fluid chromatography provides the corresponding (2R,5R)- and (2S,5S)-isomers. 72 WO 2009/016498 PCT/IB2008/002046 CHART M 0 OH L2 0 O H 0 TsO"". O TsO O OH Mi M2 5 CHARTN -O 0 0 HO 0 0 0 0 0- 0 0 0 NI N2 TsO 0 0 N2 i O 0 N3 Additional examples of G-X may be prepared as described below. According to Chart M, (5,5 10 bis(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (M2) is prepared from rac ((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (L2) by oxidation under Swern conditions to afford M1 which is then reacted with formaldehyde under basic conditions. According to Chart N, rac-(2S*,5R*)-methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (N3) is prepared from trans-dimethyl 1,4-dioxane-2,5-dicarboxylate (N1) (Summerbell, R. K. J. Am. Chem. 15 Soc. 1954, 76, 6401-6407) by first partial saponification to provide carboxylic acid N2. Subsequent reduction of the carboxylic acid functional group with borane dimethylsulfide followed by the reaction of the resulting alcohol with p-toluenesulfonyl chloride in pyridine affords N3. 73 WO 2009/016498 PCT/IB2008/002046 CHART 0 r10 0 ON O >-CN 01 02 MeO MeO CN :i0O CN 04 03 H CN 0 N OH 05 06 NO, NC OTs 07 5 According to Chart 0, (trans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate (07) is prepared by reacting 1,4-dioxa-spiro[4.5]decan-8-one with tosyl-methyl-isocyanide in the presence of potassium t butoxide to afford 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (02). Acidic hydrolysis of the resulting ketal followed by Wittig olefination with methoxy methyl triphenylphosphonium ylide and acid hydrolysis provides trans-4-formylcyclohexanecarbonitrile (05). Reduction of the aldehyde functional 10 group with sodium borohydride and reaction of the resulting alcohol with p-toluenesulfonyl chloride in pyridine affords 07. 74 WO 2009/016498 PCT/IB2008/002046 CHART P HO 0 TsO O P1 P2 TsO TsO P4 P3 TsO -C OHH P5 5 According to Chart P, cis- and trans-(4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl 4 methylbenzenesulfonate (P5) may be prepared by reacting 1,4-dioxaspiro[4.5]dec-8-ylmethanol with p-toluenesulfonyl chloride in pyridine to afford P2. The resulting ketal is subjected to acidic hydrolysis to provide (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate (P3). Epoxidation of ketone P3 with trimethylsulfoxonium ylide affords P4 which upon acid promoted oxirane ring opening provides P5. 10 75 WO 2009/016498 PCT/IB2008/002046 CHART Q 0 0 0 OtoO 04 Q1 Q2 OH HO 0 0H Q4 Q3 O H OiTs AcO AcO Os Q5 Q6 5 According to Chart Q, reagents of the formula G-X including 6-(iodomethyl)-tetrahydro-2H-pyran-3 yl)methanol (Q4) and (5-((tosyloxy)methyl)-tetrahydro-2H-pyran-2-yl)methyl acetate (Q6) may be prepared starting from diethylmalonate. 6-(lodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Q4) is prepared analogous to previously described procedures in which diethylmalonate is alkylated with 1 bromo-3-butene to afford Q2 (Deleris, G. Tetrahedron 1988, 44, 4243-4258) and then subsequently 10 Q2 is reduced with lithium aluminium hydride to afford 2-(but-3-enyl)propane-1,3-diol (Q3) (Ramos Tombo, G. M. Tetrahedron Lett. 1986, 27, 5707-5710). Cyclization of Q3 by reaction with iodine and sodium bicarbonate provides Q4 as a mixture of diastereomers (PCT Application W02005/080317). The individual isomers of Q4 may be obtained through separation by chiral supercritical fluid chromatography. 6-(Iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Q4) may be further reacted with 15 an acetate salt to afford Q5. The resulting alcohol is treated with p-toluenesulfonyl chloride in the presence of an amine base to provide (5-((tosyloxy)methyl)-tetrahydro-2H-pyran-2-yl)methyl acetate (Q6). 76 WO 2009/016498 PCT/IB2008/002046 CHART R HO TsO O 0 RI R2 TsO TsO 0 '0 ."OH 0 0 R4 R3 TsO TsO OH 0 OH R5 R6 5 According to Chart R, reagents of the formula G-X including rac-((2R*,5S*)-5-hydroxy-tetrahydro-2H pyran-2-yl)methyl 4-methylbenzenesulfonate (R3) and (5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H pyran-2-yl)methyl 4-methylbenzenesulfonate (R6) may be prepared. (3,4-Dihydro-2H-pyran-2 yl)methanol (R1) is treated with p-toluenesulfonyl chloride in pyridine to afford sulfonylester R2. Analogous to literature precedent (Zhang, S. Bioorg. Med. Chem. 2006, 14, 3953-3966), reaction of 10 R2 under hydroboration/oxidation conditions (BH 3 , NaOH, H 2 0 2 ) affords rac-((2R*,5S*)-5-hydroxy tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (R3). Oxidation of R3 under Swern conditions provides (5-oxo-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (R4). Epoxidation of ketone R4 with trimethylsulfoxonium ylide affords R5 which upon acid promoted oxirane ring opening provides R6. 15 77 WO 2009/016498 PCT/IB2008/002046 CHART S 0O i
H
3 C S1 oO 0 HO
H
3 C S3 S2 HO TsO S4 S5 5 According to Chart S, rel-(1R,2S,4S)-7-oxa-bicyclo[2.2.1]heptan-2-ylmethyl 4-methylbenzenesulfonate may be prepared by initially reacting furan with ethyl acrylate in the presence of zinc iodide to afford the cycloadduct S1. Alkene S1 is then treated with hydrogen and palladium on carbon in ethanol to provide a mixture of isomers which are separated by silica gel chromatography to afford S2. Saponification of S2 with aqueous sodium hydroxide provides carboxylic acid S3 which may be 10 reacted with 1,1'-carbonyldiimidazole and sodium borohydride to afford alcohol S4. The desired tosylate S5 is provided by reacting the resulting alcohol with p-toluenesulfonyl chloride in the presence of an amine base. By employing these same procedures and the other S2 isomer separated by chromatography, rel-(1 R,2S,4 S)-7-oxa-bicyclo{2.2.1 )heptan-2-ylmethyl 4-methylbenzenesulfonate may be prepared. 15 78 WO 2009/016498 PCT/IB2008/002046 CHART T 0 0 HO
--
NH : HO NHO 00 T1 T2 TsO NH HO NH 0 0 T4 T3 5 According to Chart T, (6-oxopiperidin-3-yl)methyl 4-methylbenzenesulfonate (T4) may be prepared by reacting 6-hydroxynicotinic acid (T1) with hydrogen in the presence of a palladium catalyst to afford carboxylic acid T2. The resulting acid is treated with 1,1'-carbonyldiimidazole and sodium borohydride to provide alcohol T3 which is then reacted with p-toluenesulfonyl chloride in the presence of an amine base to provide tosylate T4. 10 CHART U O 0 0 R'N R, N R'N HO O HO TsO UI U2 U3 15 According to Chart U, reagents of the formula G-X may be prepared where lactam carboxylic acids of the formula U1 (where R may include but is not limited to hydrogen, methyl, ethyl, and iso-propyl) obtained as described by E. Valentin et. al. (Tetrahedron Asymmetry, 2001, 12, 3241-3249) are reacted with 1,1'-carbonyldiimidazole and sodium borohydride to provide alcohols of the formula U2. The resulting alcohols are reacted with p-toluenesulfonyl chloride in the presence of an amine base to 20 provide tosylates of the formula U3. 79 WO 2009/016498 PCT/IB2008/002046 CHART V 0 O
NH
2
CH
3 N H3C 7 H 3 0" V1 V2 -OHH N V2 10 N 0 O
H
3 C' V3 V4 5 According to Chart V, (S)-N-Boc 3-(hydroxymethyl)pyrrolidine (V4) is prepared from (R)-1 phenylethanamine by cyclization with dimethyl 2-oxosuccinate in refluxing toluene to provide V2. Lactam V2 is then reduced with lithium aluminium hydride to provide ((S)-1-((S)-1 phenylethyl)pyrrolidin-3-yl)methanol (V3). The alcohol is reacted with hydrogen gas in the presence of Pd(OH) 2 on carbon, and the resulting amine is treated with di-tert-butyl dicarbonate to provide V4. In a 10 similar manner, (R)-N-Boc 3-(hydroxymethyl)pyrrolidine is prepared from (S)-1-phenylethanamine. CHART W S O- i S CN W1 OH OH W2 W3 W3 : TsO W4 15 80 WO 2009/016498 PCT/IB2008/002046 According to Chart W, reagents of the formula G-X specifically (tetrahydro-2H-thiopyran-4-yl)methyl 4 methylbenzenesulfonate (W4) may be prepared. Tetrahydrothiopyran-4-one is reacted with lithium chloride and samarium diiodide to afford tetrahydro-2H-thiopyran-4-carbonitrile (W1) which is then hydrolyzed under basic conditions (e.g. NaOH) to provide the corresponding carboxylic acid W2. The 5 carboxylic acid is reacted with 1,1'-carbonyldiimidazole and sodium borohydride to provide alcohol W3. Tosylate W4 is then prepared by treating W3 with p-toluenesulfonyl chloride in the presence of an amine base. CHART X 10 HO MeO OH ' r NCH3 o I H 0 x1 0 X1 Boc' NMeA MeO O OH X2 0 X2 N' Bn N ' Bn HN OH HN OH 0 X3 X4 N'Bn R 0 X5 According to Chart X, reagents of the formula G-X as depicted in formula X5 may be prepared. L Serine methyl ester is treated with benzaldehyde and NaBH(OAc) 3 to afford benzylamine XI which is 15 subsequently coupled (BDP, 1-HOBT, diisopropylethylamine) with N-(tert-butoxycarbonyl)glycine to provide X2. The tert-butylcarbamate is removed under acidic conditions (HCI/chloroform) and the resulting product is cyclized under basic conditions (5% aq. NaHCO 3 ) to provide piperizine-2,5-dione X3. Piperizine X4 is then prepared by reduction of X3 with a metal hydride (e.g. lithium aluminium hydride) and the product is subsequently reacted with alkyl sulfonyl chlorides in the presence of an 20 amine base to provide compounds of the formula X5 where R may be but is not limited to methyl, ethyl, propyl, and iso-propyl. 81 WO 2009/016498 PCT/IB2008/002046 CHART Y 0 0 K Y2 L Q 0 N Y WNH I HO X 0 K K Y1 Y3 L L Q Q O N Y N Y W.NH W'NH X=OH F X =NH 2 CN K Y4 L Q N Y NH 5 Compounds of the general formula Y1 and Y2 (wherein J and K are independently CH 2 or 0) may be further elaborated as described in Chart Y. Compounds of the formula Y1 may be oxidized to the carboxylic acid by reaction with an appropriate oxidizing agent (e.g. pyridinium dichromate) to provide Y3 (X = OH). Similarly, saponification of compounds of the formula Y2 under basic conditions (e.g. sodium hydroxide) may provide compounds of the formula Y3 (X = OH). Treatment of the resulting 10 carboxylic acids Y3 with oxalyl chloride followed by reaction with ammonia affords the primary amides 82 WO 2009/016498 PCT/IB2008/002046 Y3 (X = NH 2 ). The primary amide may then be reacted with a strong dehydrating agent (e.g. POCl 3 ) to provide nitriles of the formula Y4. CHART Z 5 X H 2 N K K ZI L L Q Q N Y O r N Y W.NH W NH X = OH Z2 X =OTs RHN K Z3 L Q O' N Y W.NH Compounds of the general formula Z1 (wherein J and K are independently CH 2 or 0) may be further elaborated as described in Chart Z. Alcohols of the formula Z1 (X = OH) may be reacted with p 10 toluenesulfonyl chloride in the presence of an amine base to afford compounds of the formula Z1 (Y = OTs). Subsequent reaction of Z1 (X = OTs) with ammonia in a solvent such as methanol provides amines of the formula Z2. The resulting amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula Z3 (R = C 1
.
6 alkyl). Alternatively, the amine Z2 may be reacted with carboxylic acid halides to provide compounds of the 15 formula Z3 (R = COR 23) or with sulfonyl chlorides to provide compounds of the formula Z3 (R =
SO
2
R
3 7 ). 83 WO 2009/016498 PCT/IB2008/002046 CHART AA H2N-- RH N 9 01 9 -1 L L Q Q O N Y O N Y W'NH W.NH AA1 AA2 5 Compounds of the general formula AA1 may be further elaborated as described in Chart AA. The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula AA2 (R = CS-ealkyl). Alternatively, the amine AA1 may be reacted with carboxylic acid halides to provide compounds of the formula AA2 (R = COR9) or with sulfonyl chlorides to provide compounds of the formula AA2 (R = S0 2
R
3 6 ). 10 CHART BB H R N N Y 01 Y )1 L L Q QQ O N Y N Y W.NH WNH BB1 BB2 15 Compounds of the general formula BB1 may be further elaborated as described in Chart BB. The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula BB2 (R = C 1 .ealkyl). Alternatively, the amine BB1 may be reacted with carboxylic acid halides to provide compounds of the formula BB2 (R = COR 9 ) or with sulfonyl chlorides to provide compounds of the formula BB2 (R = SO 2 R 12). 20 84 WO 2009/016498 PCT/IB2008/002046 CHART CC HN RN X X L L Q Q O N Y N Y W.NH W.NH CC1 CC2 5 Compounds of the general formula CC1 (where X is CH 2 or 0) may be further elaborated as described in Chart CC. The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula CC2 (R = C 1 ealkyl). Alternatively, the amine CC1 may be reacted with carboxylic acid halides to provide compounds of the formula CC2 (R = R 9 ) or with sulfonyl chlorides to provide compounds of the formula CC2 (R = R2). 10 CHART DD 0"0 S , L L a 10 Q Q O -N Y N Y W.NH WNH DDI DD2 15 As described in Chart DD, compounds of the formula DD1 may be oxidized in the presence of oxone to provide tetrahydrothiopyran-1,1-dione derivatives of the formula DD2. 85 WO 2009/016498 PCT/IB2008/002046 CHART EE H H .N 0 .N 0 W N N N N Y Q -'OH Y Q CN
NH
2 EE1 EE2 H H N 0 .N 0 W W N' N O N N, Y Q G Y Q '0 G
N-
0 NH 2 EE4 EE3 5 Compounds of formula (1) in which L is an oxadiazole ring may be prepared as described in Chart EE. Nitriles of the formula EE1 obtained as described in Chart C and Chart G above are treated with hydroxylamine hydrochloride under basic conditions (e.g. sodium hydroxide) to provide compounds of the formula EE2. Compounds EE2 are then reacted with compounds of the formula G-CO 2 H in the presence of an activating agent (e.g. N-hydroxybenzotriazole) and a coupling reagent (e.g. polymer 10 supported carbodiimide resin) to afford compounds of the formula EE3 which upon heating in the presence of a base provide EE4. 86 WO 2009/016498 PCT/IB2008/002046 CHART FF 1-1 0 1-1 0 Y N Cl Y N C4 FF1 SiR3 H N 0 HO 0 N N Y N Y N FF3 FF2 H WN 0 N Y N -'N--G Nz:N FF4 5 Compounds of formula (I) in which L is a 1,2,3-triazole ring, M is N, and Q is N may be prepared as described in Chart FF. Esters of the formula C4 obtained as described in Chart C are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, isopropyl) under Sonogashira coupling conditions (e.g. catalytic Cul, Ph 3 P, and (Ph 3
P)
2 PdCI 2 ) to provide alkynes FF1 which are subsequently treated with lithium hydroxide to afford carboxylic acids of the formula FF2. Treatment of 10 FF2 with a primary amine of the formula W-NH 2 in the presence of O-(7-azabenzotriazol-1-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate provides amides of the formula FF3. Cyclization of FF3 with azides of the formula G-N 3 in the presence of catalytic copper(II) sulfate and sodium ascorbate provide 1,2,3-triazoles of the formula FF4. 87 WO 2009/016498 PCT/IB2008/002046 CHART GG H S 0 .N O N' 10 N' Y N OH Y N OH C3 GGI H N 0 H W N 0 W Y NN SiR 3 Y N Cl GG3 GG2 H H WN 0 W.N O Y N Y N -'N--G N N GG4 FF4 5 Compounds of formula (1) in which L is a 1,2,3-triazole ring, M is N, and 0 is N may be prepared as described in Chart GG. Esters of the formula C3 obtained as described in Chart C are reacted with a primary amine of the formula W-NH 2 to provide amides of the formula GG1. Treatment of hydroxypyrimidines GG1 with oxalyl chloride/DMF affords chloropyrimidines of the formula GG2. Amides GG2 are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, 10 isopropyl) under Sonogashira coupling conditions (e.g. catalytic Cul, Ph 3 P, and (Ph 3
P)
2 PdCI 2 ) to provide alkynes GG3, which are subsequently treated with a fluoride ion source (e.g. potassium fluoride) to afford terminal alkynes of the formula GG4. Cyclization of GG4 with azides of the formula
G-N
3 in the presence of catalytic copper(II) sulfate and sodium ascorbate provide 1,2,3-triazoles of the formula FF4. 15 88 WO 2009/016498 PCT/IB2008/002046 CHART HH N'0 , O 0 Y N Y N FF1 SiR3 HHI HO 0 O 0 N' N' Y N /N-G Y N-G N=N'N N' HH3 HH2 H N 0 W N Y N N-G Nz:N FF4 5 Compounds of formula (1) in which L is a 1,2,3-triazole ring, M is N, and Q is N may be prepared as described in Chart HH. Esters of the formula FF1 obtained as described in Chart FF are reacted with a fluoride ion source (e.g. potassium fluoride) to afford terminal alkynes of the formula HH1. Cyclization of HH1 with azides of the formula G-N 3 in the presence of catalytic copper(II) sulfate and sodium ascorbate provide 1,2,3-triazoles of the formula HH2 which are subsequently treated with 10 lithium hydroxide to afford carboxylic acids of the formula HH3. Treatment of HH3 with a primary amine of the formula W-NH 2 in the presence of 0-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate provides amides of the formula FF4. 89 WO 2009/016498 PCT/IB2008/002046 CHART || 1-0 0 1 0 N N Y N Cl Y N C4 SiR 3 C4 Ili l HO 0 HO 0 NN Y N - N-G N Y N N N4 113 112 H N 0 N Y N N-G N Ni FF4 5 Compounds of formula (1) in which L is a 1,2,3-triazole ring, M is N, and Q is N may be prepared as described in Chart II, Esters of the formula C4 obtained as described in Chart C are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, isopropyl) under Sonogashira coupling conditions (e.g. catalytic Cul, Ph 3 P, and (Ph 3
P)
2 PdCI 2 ) to provide alkynes |1l, which are subsequently treated with lithium hydroxide to afford carboxylic acids of the formula 112. Cyclization of 10 112 with azides of the formula G-N 3 in the presence of catalytic copper(ll) sulfate and sodium ascorbate provide 1,2,3-triazoles of the formula 113. Treatment of 113 with a primary amine of the formula W-NH 2 in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate provides amides of the formula FF4. 15 Azides of the formula G-N 3 employed in Charts FF - Il may be prepared alcohols G-OH obtained commercially or prepared as described in Charts J - X. For example, the alcohol G-OH may be converted to a sulfonate ester which is then subjected to substitution by a nucleophilic azide source (e.g. sodium azide). 90 WO 2009/016498 PCT/IB2008/002046 CHART JJ OTs Cl Cl HO HO C1 O 0 Ph0 Ph JJI JJ2 JJ3 OTs HO TsO TsO HO" 0 0 O 0 0 0 O 0 0 QPh QPh QPh OH JJ3 JJ4 JJ5 JJ6 5 Reagents of the formula G-X such as ((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methy 4 methylbenzenesulfonate (JJ6) may be prepared as described in Chart JJ. R-Epichlorohydrin, JJ1, was reacted with benzyl alcohol using boron trifluoride etherate as an acid catalyst to provide the alcohol of formula JJ2. The alcohol of formula JJ2 was reacted with the S-glycidol tosylate using boron trifluoride etherate as an acid catalyst to provide the alcohol of formula JJ3. The alcohol of formula JJ3 10 was cyclized under basic conditions (e.g., aqueous sodium hydroxide) to provide the alcohol of formula JJ4. The alcohol of formula JJ4 was reacted with p-toluenesulfonyl chloride in the presence of an amine base (e.g., pyridine) to provide the tosylate of formula JJ5. The benzyl ether of formula JJ5 was reacted with hydrogen gas in the presence of palladium on carbon to provide the alcohol of formula JJ6. 15 CHART KK H N O W.N 0 W N 0N Y N Y N FF3 KKI 20 Compounds of formula (1) in which L is an isoxazole ring, M is N, and Q is N may be prepared as described in Chart KK. Alkynes of the formula FF3 described in Chart FF may be reacted with 2 91 WO 2009/016498 PCT/IB2008/002046 chloro-2-(hydroxyimino)-derivatives of the formula G-C(NOH)-Cl in the presence of an amine base (e.g. triethylamine) in toluene at temperatures from 20 - 110 *C. The chloro-hydroxyimines are readily prepared from the corresponding aldehydes by reaction with hydroxylamine hydrochloride and sodium acetate followed by chlorination by N-chlorosuccinimide. 5 CHART LL X 0 0 NR 3 8
R
3 9 K K Y3 LL1 L L Q Q O -N Y O 'N Y W.NH WNH 10 Compounds of the general formula Y3 (wherein X is OH, J and K are independently CH 2 or 0) may be further elaborated as described in Chart LL. Compounds of the formula Y3 (X = OH) may be reacted with an amine of the general formula HNR 3 R39 in the presence of 1,1'-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to afford amides of the general formula LL1. 15 CHART MM LG LG L" G Q Q Q 0 ' N ON Y N Y N Y 'O HO .NH MMI MM2 MM3 Compounds of the general formula MM1 (wherein R is an alkyl group) may be elaborated as 20 described in Chart MM. Esters of the formula MM1 may be reacted with an inorganic base (e.g. sodium hydroxide, lithium hydroxide) in a mixture of water and an organic solvent (e.g. tetrahydrofuran) to afford carboxylic acids of the formula MM2. Carboxylic acids of the formula MM2 may be reacted with an amine of the formula W-NH 2 in the presence of a suitable carboxylic acid activating agent (e.g. 1,1 '-carbonyldiimidazole, 1 -hydroxybenzotriazole/1 -ethyl-3-(3' 25 dimethylaminopropyl)carbodimide hydrochloride) to afford amides of the formula MM3. Alternatively, esters of the formula MM1 (wherein R is methyl or ethyl) may be reacted with an amine of the formula
W-NH
2 at temperatures of 20 - 100 *C either neat or in a minimal amount of an organic solvent (e.g. 92 WO 2009/016498 PCT/IB2008/002046 methanol, tetrahydrofuran, and N,N-dimethylformamide) to provide amides of the formula MM3 directly. CHART NN X SR 23 K K NNI L L Q Q N Y N Y R'O R' X = OH NN2 X = OTs S02
R
3 7 K NN3 L Q O" N Y 5 R' Compounds of the general formula NN1 (wherein R is alkyl, J and K are independently CH 2 or 0) may be further elaborated as described in Chart NN. Alcohols of the formula NN1 (X = OH) may be reacted with p-toluenesulfonyl chloride in the presence of an amine base to afford compounds of the 10 formula NN1 (Y = OTs). Subsequent reaction of NN1 (X = OTs) with the sodium salt of thioalkoxides of the formula HSR to afford compounds of the formula NN2. Sulfides of the formula NN2 may be oxidized by 3-chloroperbenzoic acid to provide sulfones of the formula NN3. Compounds of formula NN2 and NN3 may be further elaborated as described in Chart MM to afford amides of Formula (1). 15 The compounds of Formula (1) may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures. Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non 20 racemic reagent followed by separation of the resulting diastereomers by common methods (e.g. 93 WO 2009/016498 PCT/IB2008/002046 crystallization, chromatographic separation, or distillation) and chemical reversion to scalemic compound, Simulated Moving Bed technology, or high/medium-pressure liquid chromatography or supercritical fluid chromatography employing a chiral stationary phase. These techniques may be performed on the final compounds of Formula (1) or on any intermediates to compounds of Formula (1) 5 which bear a stereogenic center. Also, to facilitate separation by any of the methods described above, the compounds of Formula (1) or any intermediates to the compounds of Formula (1) which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques. 10 Detailed Preparative Methods The detailed examples below illustrate preparation of compounds of this invention. Other compounds of this invention may be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art. The following examples are merely illustrative, and not limiting to the remainder of this disclosure in any way. 15 Example 1 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazo-5 yl)pyrimidine-4-carboxamide F N 0 -P HN -O NNH 2 Step 1: Preparation of methyl 6-cyanopyrim idine-4-carboxylate 0 20 N Commercially available methyl 6-chloropyrimidine-4-carboxylate (1.00 g, 5.80 mmol) was taken up in dichloromethane (20 mL) and then treated with tetraethyl ammonium cyanide (0.996 g, 6.37 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.13 g, 1.2 mmol). The reaction was allowed to stir at room temperature for 0.5 h. The reaction was diluted with diethyl ether (40 mL) then washed with 25 water (1 x 25 mL) and brine (1 x 40 mL). The organics were poured onto a silica plug (20 g) and eluted with diethyl ether (200 mL) to afford the title compound as an orange oil (0.85 g, 90%). LC/MS (5% 95% CH 3
CN/H
2 0, 6 min): 0.267 min, m/z 164 (M+Na). 94 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of methyl 6-(2H-tetrazol-5-yl)p yrimidine-4-carboxylate 0 0 N \---N N'-NH Methyl 6-cyanopyrimidine-4-carboxylate (1.43 g, 8.77 mmol) was taken up in methanol (40 mL) and treated with sodium azide (598 mg, 9.20 mmol) and zinc (II) bromide (1.97 g, 8.77 mmol). 5 The reaction was stirred at room temperature for 15 h and then was concentrated. This residue was diluted with water (8 mL) and 1 N aqueous hydrochloric acid (40 mL) and stirred one hour. The resulting slurry was filtered with the solids washed with water (10 mL) and dried in vacuo to afford the title compound as a yellow solid (1.37 g, 76%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 0.54 min, m/z 207 (M+H). 10 Step 3. Preparation of 4-fluoro-3-methoxybenzylamine hydrochloride "I")
NH
2 HCI F A 2G Parr reactor (4842) was charged with 4-fluoro-3-methoxy-benzonitrile (133.0 g, 0.88 mol), ethanol (3550 mL), concentrated hydrochloric acid (396 ml, 4.75 mol) and 10% Pd/C with 50% water (13.3 g). The resulting mixture was stirred with heating at 30-33 0C under hydrogen pressure 15 (40-50 psi, first 2 hours refill hydrogen every 20 min) overnight. The reaction mixture was cooled to room temperature, filtered through Celite T and the filtrate concentrated. The residue obtained was treated with acetonitrile (250 mL) and the white solid was filtered, washed with cold acetonitrile and vacuum dried to afford the title compound (140 g, 83%). MS (ES+) m/z 156 (M+H). Elemental analysis found: C, 49.97; H, 6.13; N, 7.59. 20 Step 4: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide F N N --N WNH Methyl 6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (0.75 g, 3.64 mmol) was taken up in dimethylacetamide (5 mL) and then treated with 4-fluoro-3-methoxybenzylamine hydrochloride (1.57 g, 8.19 mmol) and triethylamine (1.5 g, 14 mmol) and left to stir for 15 hours at room temperature. The 25 mixture was diluted with 1 N aqueous NaOH (15 mL) and then washed with diethyl ether (2 x 10 mL). The mixture was then adjusted to pH 3 with concentrated Hydrochloric acid and stirred with ethyl acetate ( 10 mL). After 1 h, the organic layer was separated and concentrated to an oil that solidified affording the title compound as a beige solid (1.05 g, 88%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.26 min, m/z 330 (M+H). 95 WO 2009/016498 PCT/IB2008/002046 Step 5: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexl)methVl)-2H tetrazol-5-yl)pyrimidine-4-carboxamide F 0 O -P HN -O N.N
NH
2 N-N N-N N-(4-Fluoro-3-methoxybenzyl)-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (0.91 g, 2.8 5 mmol) and commercially available tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (760 mg, 3.32 mmol) were taken up in tetrahydrofuran (20 mL) and treated with polymer supported triphenylphosphine (1.54 g, 3.32 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (954 mg, 4.15 mmol) was added. After 15 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated to a crude oily residue. The residue was 10 purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1% methanol ran through entire gradient) to afford the protected amine as a mixture of regioisomers ( 0.97 g, 65%, 1.80 mmol) which was subsequently dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (2.0 mL, 15 mmol). After the reaction was stirred at ambient temperature for 3 h, the mixture was diluted with dichloromethane (5 mL) and neutralized with 2.5 N aqueous NaOH to 15 achieve pH 7-8. The organic layer was separated and washed with water (3 mL), dried over sodium sulfate, and concentrated to afford the title compound (0.87 g, 72%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.06 min, m/z 441 (M+H). Example 2 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4-((methylsulfonyl)amino)cyclohexyl)methyl)-2H 20 tetrazol-5-yl)pyrimidine-4-carboxamide F 0 O -P HN H -0 N tN: N NN/0 \-N N-N C).O N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in Example 1) (0.870 g, 1.98 mmol) was taken up in dichloromethane (5 mL) and treated with methane sulfonyl chloride ( 0.17 mL, 2.1 mmol) and 25 triethylamine (0.30 mL, 2.2 mmol). After 1 h at room temperature, the reaction was concentrated. The residue was purified via reverse phase chromatography (4-60% acetonitrile/water over 45 minutes) with the first eluted compound was isolated to afford the title compound as a white solid (143 mg, 14%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.98 min, m/z 519 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.04 - 1.25 (m, 4 H), 1.61 (br. s., 2 H), 1.83 - 1.99 (m, 3 H), 2.83 (s, 3 H), 3.00 (br. s., 1 H), 3.78 30 (s, 3 H), 4.46 (d, J=6.0 Hz, 2 H), 4.66 (d, J=6.6 Hz, 2 H), 6.89 (d, J=7.3 Hz, 2 H), 7.03 - 7.21 (m, 2 H), 8.56 (s, 1 H), 9.46 (s, 1 H), 9.61 (t, J=6.1 Hz, 1 H). 96 WO 2009/016498 PCT/IB2008/002046 Example 3 N-(3-Chloro-4-fluorobenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine 4-carboxamide F N Cl / NzN
NH
2
NX
N\-N N' C 5 Step 1: Preparation of N-(3-chloro-4-fluorobenzyl)-6-(2H-tetrazol-5-l)pyrimidine-4-carboxamide F P -HN0 Cl N NN N X \ , I \N N'NH Methyl 6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide, Example 1) (0.72 g, 3.49 mmol) was taken up in dimethylacetamide (5 10 mL), treated with commercially available (4-fluoro-3-chlorophenyl)methanamine (1.23 g, 7.68 mmol) and triethylamine (1.95 g, 14 mmol), and left to stir for 15 hours at room temperature. The mixture was diluted with 1 N aqueous NaOH (15 mL) and then washed with diethyl ether (2 x 10 mL). The mixture was then adjusted to pH 3 with concentrated Hydrochloric acid, stirred with ethyl acetate (10 mL), and filtered to afford the title compound as a pale yellow solid (0.71 g, 61%). LC/MS (5%-95% CH 3
CN/H
2 0, 15 6 min): 2.19 min, m/z 334 (M+H). Step 2: Preparation of N-(3-chloro-4-fluorobenzyl)-6-(2-((trans-4-aminocyclohexvl)methyl)-2H-tetrazol 5-vl)pyrimidine-4-carboxamide F -P H\ 0 -FHN Cl NZN
NH
2 N N N' N-(4-Fluoro-3-chlorobenzyl)-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (0.71 g, 2.1 mmol) 20 and commercially available tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (585 mg, 2.55 mmol) were taken up in tetrahydrofuran (20 mL) and treated with polymer supported triphenylphosphine (1.19 g, 2.55 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (735 mg, 3.19 mmol) was added. After 15 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated to a crude oily residue, The residue was 25 purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1% methanol ran through entire gradient) to afford the protected amine (1.08 g, 93%, 1.99 mmol) which was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (2.0 mL, 15 mmol). After the reaction was stirred at ambient temperature for 3 h, the mixture was diluted with dichloromethane (5 mL) and neutralized with 2.5 N aqueous NaOH to achieve pH 7-8. The organic layer was 97 WO 2009/016498 PCT/IB2008/002046 separated, washed with water (3 mL), then dried over sodium sulfate, and concentrated to afford the title compound as an amber oil (0.87 g, 92%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.24 min, m/z 445 (M+H). Example 4 5 N-(3-Chloro-4-fluorobenzyl)-6-(2-((trans-4-((methylsulfonyl)amino)cyclohexy)methyl)-2H tetrazol-5-yl)pyrimidine-4-carboxamide F 0 -P HN Cl H N NCIO NN N N-(3-Chloro-4-fluorobenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in Example 3) (0.87 g, 2.0 mmol) was taken up in 10 dichloromethane (5 mL) and treated with methane sulfonyl chloride (0.17 mL, 2.1 mmol) and triethylamine (0.30 mL, 2.2 mmol). After 1 h at room temperature, the reaction was concentrated to a crude residue. The residue was purified via reverse phase chromatography (4-60% acetonitrile/water over 45 minutes). The first eluted compound was isolated to afford the title compound as a white solid (105 mg, 10%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 4.22 min, m/z 523 (M+H). 'H NMR (400 MHz, 15 DMSO-d 6 ) 6 ppm 1.04 - 1.27 (m, 4 H), 1.59 (d, J=10.8 Hz, 2 H), 1.80 - 1.98 (m, 3 H), 2.83 (s, 3 H), 3.01 (d, J=6.8 Hz, 1 H), 4.48 (d, J=6.2 Hz, 2 H), 4.66 (d, J=6.8 Hz, 2 H), 6.89 (d, J=7.3 Hz, 1 H), 7.25 7.36 (m, 2 H), 7.48 - 7.58 (m, 1 H), 8.55 (d, J=1.3 Hz, 1 H), 9.46 (d, J=1.1 Hz, 1 H), 9.71 (t, J=6.3 Hz, 1 H). Example 5 20 N-(3-Methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide N -O NzN NH2 N N NN Step 1: Preparation of 6-chloro-2-methylpyrimidin-4-ol HO CI N,, N 25 To a 0 *C solution of 13M sulfuric acid (1.2 L, 15.6 mol) was added portion-wise solid 4,6 dichloro-2-methylpyrimidine (475 g, 2.91 mol). The resulting mixture was allowed to warm to room temperature over 1.5 hours. The solution was poured into a well stirred iced solution of 6N NaOH (3.6 L, 21.6 mol). The resulting solids were then collected by vacuum filtration and washed with warm 98 WO 2009/016498 PCT/IB2008/002046 water (3 x 1 L). High vacuum drying at 35 0C provided the title compound as a white solid (393.4 g, 93%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min) 0.95 min, m/z 145 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 12.81 (br. s, 1 H), 6.30 (s, 1 H), 2.26 (s, 3 H). Step 2: Preparation of methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate 0 NO OH N -N 5 6-Chloro-2-methylpyrimidin-4-ol (36.7 g, 254 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride (10.4 g, 12.7 mmol), and diisopropylethylamine (49.2 g, 381 mmol) were combined in methanol (254 mL). The reaction was heated to 85 *C in the presence of carbon monoxide (10.7 g, 381 mmol, 50 psi) for 24 hours. The reaction was allowed to cool to room 10 temperature and the resulting solids collected by vacuum filtration. The solids were rinsed with methanol (100 mL) and diethyl ether (2 x 100 mL). Vacuum drying provided the title compound as a brown solid (38.7 g, 91%). LC/MS (5%-95% CH 3
CN/H
2 0, 3 min: 0.29 min, m/z 169 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 12.79 (br. s, 1 H), 6.68 (s, 1 H), 3.79 (s, 3 H), 2.29 (s, 3 H), Step 3: Preparation of methyl 6-chloro-2-methylpyrimidine-4-carboxylate 0 NO Cl N - N 15 Methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate (30.0 g, 178 mmol) was dissolved in dichloromethane (446 mL). Oxalyl chloride (18.6 mL, 1.2 equiv) was added followed by addition of N,N-dimethylacetamide (3.5 mL, 0.25 equiv). The mixture was heated to reflux for 2 hours. After cooling to room temperature, the insolubles were removed by filtration and the filtrate partially 20 concentrated. Purification by silica gel chromatography (35/65, ethyl acetate/heptane) provided the title compound as a white solid (26.6 g, 80%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min: 1.59 min, m/z 187 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.90 (s, 1 H), 3.88 (s, 3 H), 2.65 (s, 3 H). Step 4: Preparation of methyl 6-cyano-2-methylpyrimidine-4-carboxylate 0 NO ~CN N ,N 25 Methyl 6-chloro-2-methylpyrimidine-4-carboxylate (30.0 g, 161 mmol) was dissolved in dichloromethane (460 mL). Tetraethylammonium cyanide (27.6 g, 177 mmol) was added followed by 1,4-diazabicyclo[2.2.2]octane (3.60 g, 32.0 mmol). The reaction was stirred for 30 min at room temperature. The reaction mixture was washed with 1N NaOH (3 x 100 mL), water (2 x 100 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to give a 99 WO 2009/016498 PCT/IB2008/002046 dark brown solid. Purification by silica gel chromatography (2/1, ethyl acetate/heptane) provided the title compound as a white crystalline solid (24.4 g, 86%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min: 0.96 min, m/z 178 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 8.38 (s, 1 H), 3.88 (s, 3 H), 2.75 (s, 3 H). Step 5: Preparation of 6-cyano-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0 SNCN 5 3-Methoxybenyzlamine (9.68 g, 70.6 mmol) and methyl 6-cyano-2-methylpyrimidine-4 carboxylate (10.0 g, 56.4 mmol) were dissolved in N,N-dimethylacetamide (113 mL). Diisopropylethylamine (25.5 g, 198 mmol) was added and the mixture heated to 100 *C for 2 hours. After cooling to room temperature, the mixture was diluted with water (250 mL) and extracted with 10 ethyl acetate (3 x 250 mL). The combined organics were then washed with brine (250 mL) and dried over sodium sulfate, filtered, and evaporated to give a red oil. Purification by silica gel chromatography (20/80, ethyl acetate/heptane) provided the title compound as a white solid (14.6 g, 92%). LC/MS (5% 95% CH 3
CN/H
2 0, 4 min: 2.49 min, m/z 283 (M+H). 1 H NMR (400 MHz, DMSO-dc,) 6 ppm 9.55 (t, J=6.2 Hz, 1 H), 8.31 (s, 1 H), 7.19 (t, J=8.1 Hz, 1 H), 6.74 - 6.89 (m, 3 H), 4.44 (d, J=6.3 Hz, 2 H), 3.69 15 (s, 3 H), 2.75 (s, 3 H). Step 6: Preparation of N-(3-methoxvbenzvl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide 0 N O N N ON ,N N 6-Cyano-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (14.2 g, 50.3 mmol), sodium azide (3.60 g, 55.3 mmol), and zinc bromide (11.3 g, 50.3 mmol) were suspended in water 20 (112 mL). The reaction was heated to reflux for 16 hours. After cooling to room temperature, 6N hydrochloric acid (180 mL) was added and the mixture stirred vigorously for 1 hour. The solids were collected by vacuum filtration and rinsed with 6N hydrochloric acid (3 x 100 mL) and water (2 x 100 mL). High vacuum drying at 55 *C provided the title compound as a white solid (15.0 g, 92%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min: 2.38 min, m/z 326 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.53 (t, 25 J=6.4 Hz, 1 H), 8.42 (s, 1 H), 7.21 (t, J=8.2 Hz, 1 H), 6.86 - 6.91 (m, 2 H), 6.76 - 6.82 (m, 1 H), 4.48 (d, J=6.6 Hz, 2 H), 3.70 (s, 3 H), 2.82 (s, 3 H). 100 WO 2009/016498 PCT/IB2008/002046 Step 7: Preparation of (trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)methy 4 methylbenzenesulfonate H p-Toluene sulfonyl chloride (1.68 g, 8.81 mmol) was added to a solution of tert-butyl trans-(4 5 hydroxymethyl)cyclohexylcarbamate (1.84 g, 8.02 mmol) in pyridine (10 mL) at 0 *C. The reaction mixture was allowed to slowly warm to room temperature. After 6 h, the mixture was cooled to 0 *C and treated with water (100 mL). The resulting precipitate was filtered, washed with cold water (2 x 20 mL), and dried in vacuo to afford the title compound as a white solid (2.91 g, 95%). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.78 (d, J=8.3 Hz, 2 H), 7.49 (d, J=8.2 Hz, 2 H), 6.69 (d, J=8.0 Hz, 1 H), 3.82 (d, 10 J=6.2 Hz, 2 H), 3.04 - 3.14 (m, 1 H), 2.43 (s, 3 H), 1.69 - 1.76 (m, 2 H), 1.57 - 1.64 (m, 2 H), 1.42 1.53 (m, 1 H), 1.36 (s, 9 H), 1.01 - 1.12 (m, 2 H), 0.85 - 0.96 (m, 2 H). Step 8: Preparation of tert-butyl trans-4-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl) 2H-tetrazol-2-yl)methvl)cvclohexylcarbamate - N -O N H H\\N 0 N NN O 15 Triethylamine (280 mg, 2.7 mmol) and (trans-4-((tet-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (530 mg, 1.38 mmol) was added to a solution of N-(3-methoxybenzyl)-2 methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (450 mg, 1.38 mmol) in anhydrous dimethylacetamide (0.5 mL). The reaction was stirred overnight at 85 0C in a capped vial. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrite) to afford the title 20 compound as a white solid (342 mg). Step 9: Preparation of N-(3-methoxvbenzyl)-6-(2-(((trans)-4-aminocyclohexvl)methyl)-2H-tetrazol-5-vl) 2-methylpyrimidine-4-carboxamide N
-
NH -o N - N ."N 4M Hydrochloric acid in dioxane (5 mL) was added to a solution of tert-butyl trans-4-((5-(6-((3 25 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate (342 mg) in acetonitrile (1.5 mL). The reaction was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was slurried 2x in ether (ether decanted off each time) and 101 WO 2009/016498 PCT/IB2008/002046 the resultant solid was dried under vacuum to afford the hydrochloride salt of the title compound as a white solid (418 mg). Example 6 N-(3-Methoxybenzyl)-2-methyl-6-(2-(((trans-4-(methylsulfonamido)cyclohexyl)methyl)-2H 5 tetrazol-5-yl)pyrimidine-4-carboxamide N O S -ON ON Triethylamine (60 mg, 0.6 mmol) and methane sulfonyl chloride (34 mg, 0.3 mmol) were added to a solution of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide (prepared as described in Example 5) (100 mg, 0.19 mmol) in 10 dichloromethane (1 mL). The reaction was stirred overnight at room temperature. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (41 mg). MS (ES+) m/z 515 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.49 (1 H, br. s.), 8.41 (1 H, s), 7.56 (1 H, br. s.), 7.22 - 7.30 (1 H, m), 6.93 (2 H, br, s.), 6.84 (1 H, br. s.), 4.70 (2 H, d, J=7.0 Hz), 4.51 (2 H, d, J=5.9 Hz), 3.74 (2 H, s), 3.05 (2 H, br. s.), 2.86 (6 H, d, J=19.8 Hz), 1.90 (3 H, 15 br. s.), 1.64 (2 H, br. s.), 1.20 (5 H, d, J=11.0 Hz). Example 7 N-(3-Methoxybenzyl)-6-(2-((trans-4-acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-2 methylpyrimidine-4-carboxamide HN 0 -0 / N\ N O~N 0 N N NN 20 Triethylamine (60 mg, 0.6 mmol) and acetic anhydride (31 mg, 0.3 mmol) were added to a solution of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 5) (100 mg, 0.19 mmol) in dichloromethane (1 mL). The reaction was stirred overnight at room temperature. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) and neutralized by passing 25 through a small carbonate column to afford the title compound as a white solid (34 mg). MS (ES+) m/z 479 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.49 (1 H, br. s.), 8.41 (1 H, s), 7.65 (1 H, d, J=7.7 Hz), 7.33 (1 H, br. s.), 7.24 (1 H, s), 6.93 (1 H, br. s.), 6.81 (1 H, br. s.), 4.70 (2 H, d, J=6.6 Hz), 4.51 (2 H, d, J=6.6 Hz), 3.74 (3 H, s), 3.46 (1 H, br. s.), 2.83 (3 H, s), 1.99 (1 H, br. s.), 1.75 (5 H, s), 1.61 (2 H, br. s.), 1.15 (5 H, d, J=10.2 Hz). 102 WO 2009/016498 PCT/IB2008/002046 Example 8 N-(3-Methoxybenzyl)-6-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y) 2-methylpyrimidine-4-carboxamide HN -O N H NN I fOH N N O 5 N-(3-Methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl )methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 5) (146 mg, 0.287 mmol), triethylamine (102 mg, 1.00 mmol) and acetoxy acetyl chloride (47 mg, 0.344 mmol) were combined in dichloromethane (4 mL). After stirring for 10 min, the mixture was concentrated and then treated with acetonitrile (2 mL) and 2.5 N sodium hydroxide (2 mL). After 1 h, the organics were removed under 10 nitrogen stream and the aqueous was adjusted to pH 6 with 10% hydrogen chloride. The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid (64.7 mg, 46%). LC/MS (10%-90% CH 3
CN/H
2 0, 6 min): 4.44 min, m/z 495 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.47 (br, s, 1 H) 8.40 (s, 1 H), 7.37 (d, J = 8.05, 1 H), 7.17-7.30 (m, 1 H), 6.91 (br. s, 2 H), 6.77 15 6.84 (m, 1 H), 5.38 (s, 1 H), 4.69 (d, J = 6.6 Hz, 2 H), 4.49 (d, J = 6.6 Hz, 2 H), 3.67 - 3.79 (m, 4 H), 3.56 (br. s., 1 H), 2.81 (s, 3 H), 1.97 (br. s., 1 H), 1.72 (br. s., 2 H), 1.60 (d, J = 11.0 Hz, 2 H), 1.09 1.33 (m, 5 H). Example 9 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 20 methylpyrimidine-4-carboxamide F N -0 /NazN "\NH2 N NN Step 1: Preparation of 6-cyano-N-(4-fluoro-3-methoxvbenzyl)-2-methylpyrimidine-4-carboxamide 0 N N OHCN 4-Fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the 25 synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide, Example 1) (13.5 g, 70.6 mmol) was dissolved in methanol (56 mL). Diisopropylethylamine (29.2 g, 226 mmol) was added and the mixture stirred for 15 minutes at room temperature. Methyl 6-cyano-2 -methylpyrimidine-4-carboxylate (prepared as described in step 4 of the 103 WO 2009/016498 PCT/IB2008/002046 synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (10.0 g, 56.4 mmol) was added and the reaction heated to 35 *C for 1 h. The methanol was removed in vacuo and the crude material partitioned between ethyl acetate (500 mL) and 1N hydrochloric acid (500 mL). The layers were separated and the aqueous 5 layer extracted with ethyl acetate (2 x 250 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (2 x 250 mL) and brine (250 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to give a brown solid. Purification by silica gel chromatography (1/2, ethyl acetate/heptane) provided the title compound as a white solid (11.7 g, 69%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min: 2.67 min, m/z 301 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 10 6 ppm 9.58 (t, J=6.2 Hz, 1 H), 8.32 (s, 1 H), 7.04 - 7.19 (m, 2 H), 6.79 - 6.90 (m, 1 H), 4.44 (d, J=6.2 Hz, 2 H), 3.78 (s, 3 H), 2.76 (s, 3 H). Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-vl)pyrimidine-4 carboxamide O N'-.N, 0 N0 N N~,NH ) I H N, F 15 6-Cyano-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (4.80 g, 16.0 mmol), sodium azide (1.14 g, 17.6 mmol), and zinc bromide (3.60 g, 16.0 mmol) were suspended in water (36 mL). The reaction was heated to reflux for 16 h. After cooling to room temperature, 6N hydrochloric acid (180 mL) was added and the mixture stirred vigorously for 1 hour. The solids were collected by vacuum filtration and rinsed with 6N hydrochloric acid (3 x 100 mL) and water (2 x 100 20 mL). High vacuum drying at 55 *C provided the title compound as a white solid (5.45 g, 99%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min: 2.56 min, m/z 344 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.55 (t, J=6.4 Hz, 1 H), 8.42 (s, 1 H), 7.06 - 7.20 (m, 2 H), 6.81 - 6.94 (m, 1 H), 4.47 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 2.82 (s, 3 H). Step 3: Preparation of tert-butVl trans-4-((5-(6-((4-fluoro-3-methoxvbenzvl)carbamoyl)-2 25 methylpyrimidin-4-yl)-2H-tetrazol-2-vl)methvl)cvclohexylcarbamate F 0 O -O N \ H N N N Triethylamine (176 mg, 1.7 mmol) and (trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)methy 4-methylbenzenesulfonate (prepared as described in step 7 of the synthesis of N-(3-methoxybenzyl) 6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, 30 Example 5) (335 mg, 0.87 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6 (2H-tetrazol-5-yl)pyrimidine-4-carboxamide (300 mg, 0.87 mmol) in anhydrous N,N-dimethylformamide (0.6 mL). The reaction was stirred overnight at 85 *C in a capped vial. The reaction mixture was 104 WO 2009/016498 PCT/IB2008/002046 purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (130 mg). Step 4: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N -P HN -O NN"N yNH2 5 N
N
A mixture of 4 M hydrochloric acid in dioxane (5 mL) and tert-butyl trans-4-((5-(6-((4-fluoro-3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate (130 mg) was stirred for 4 h at room temperature. The solvent was removed under a stream of nitrogen. The residue was slurried in ether (2x), decanting each time. The resultant solid was dried under 10 vacuum to afford the hydrochoride salt of the title compound as a white solid (135 mg). Example 10 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((trans-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)pyrimidine-4-carboxamide F -- 0 - HN I 'S -O N H/ O'l N N 15 Triethylamine (60 mg, 0.6 mmol) and methane sulfonyl chloride (34 mg, 0.3 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 9) (70 mg, 0.14 mmol) in dichloromethane (1 mL). The reaction was stirred overnight at room temperature. The product was isolated by reverse phase preparative HPLC (water/acetonitrile) to afford the title 20 compound as a white solid (37 mg). MS (ES+) m/z 533 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.51 (1 H, t, J=6.0 Hz), 8.42 (1 H, s), 7.11 - 7.21 (1 H, m), 7.18 (1 H, d, J=9.2 Hz), 6.94 (2 H, d, J=7.3 Hz), 4.70 (2 H, d, J=7.0 Hz), 4.50 (2 H, d, J=5.9 Hz), 3.82 (3 H, s), 3.05 (1 H, br. s.), 2.88 (3 H, s), 2.83 (3 H, s), 1.91 (3 H, d, J=10.2 Hz), 1.64 (2 H, br. s.), 1.26 (1 H, br. s.), 1.19 (3 H, d, J=10.6 Hz), 1.15 (1 H, br. s.). 25 Example 11 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((trans-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 105 WO 2009/016498 PCT/IB2008/002046 F 0 -P HN -N N H N N-N Triethylamine (60 mg, 0.6 mmol) and acetic anhydride (31 mg, 0.3 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 9) (65 mg, 0.13 mmol) in 5 dichloromethane (1 mL). The reaction was stirred overnight at room temperature. The product was isolated by reverse phase preparative HPLC (water/acetonitrile) and neutralized by passing through a small carbonate column to afford the title compound as a white solid (51 mg). MS (ES+) m/z 497 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.51 (1 H, t, J=5.7 Hz), 8.42 (1 H, s), 7.66 (1 H, d, J=7.7 Hz), 7.11 - 7.21 (1 H, m), 7.18 (1 H, d, J=8.8 Hz), 6.90 (1 H, d, J=7.3 Hz), 4.70 (2 H, d, J=7.0 Hz), 4.50 10 (2 H, d, J=5.9 Hz), 3.82 (3 H, s), 3.46 (1 H, br. s.), 2.83 (3 H, s), 1.99 (1 H, br. s.), 1.75 (4 H, s), 1.80 (1 H, br. s.), 1.61 (2 H, d, J=9.5 Hz), 1.25 (1 H, d, J=5.5 Hz), 1.15 (3 H, d, J=9.5 Hz), 1.10 - 1.21 (1 H, m). Example 12 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N -O N H N I O 15 N N N OH N NN0 15 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 9) (108 mg, 0.238 mmol), triethylamine (84.2 mg, 0.832 mmol) and acetoxy acetyl chloride (38.9 mg, 0.285 mmol) were combined in dichloromethane (4 mL) and stirred for 10 min. The mixture was concentrated and then 20 treated with acetonitrile (2 mL) and 2.5 N sodium hydroxide (2 mL). After 1 hour, the organics were removed under nitrogen stream and the aqueous solution was adjusted to pH 6 with 10% hydrogen chloride. The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an white solid (76 mg, 62%). LC/MS (10%-90% CH 3
CN/H
2 0, 6 min): 4.44 min, m/z 495 (M+H). 'H NMR (400 MHz, 25 DMSO-d) 6 ppm 9.35 - 9.54 (m, 1 H), 8.40 (s, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.04-7.22 (m, 1 H), 6.89 (br. s, 1 H), 5.34 (s, 1 H), 4.68 (d, J= 6.6 Hz, 2 H), 4.48 (d, J = 5.9 Hz, 2 H), 3.77 - 3.85 (m, 3 H), 3.73 (d, J = 5.9 Hz, 2 H), 3.53 (br. s., 1 H), 2.81 (s, 3 H), 1.98 (br. s., 1 H), 1.73 (d, J = 10.3 Hz, 2 H), 1.60 (d, J = 10.3 Hz, 2 H), 1.06 - 1.36 (m, 5 H). Example 13 30 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazoI-5-yi)-2 methylpyrimidine-4-carboxamide 106 WO 2009/016498 PCT/IB2008/002046 HO 0 N N NH - NH 2 O N Step 1: Preparation of 2-(3-((benzylamino)methyl)phenoxV)ethanol HO ON I 05 H A solution of 3-(2-hydroxyethoxy) benzaldehyde (10.00 g; 60.18 mmol) in anhydrous THF (230 5 mL) was treated at room temperature with benzyl amine (6.90 ml, 63.19 mmol) as a bolus and the resulting yellow solution was stirred at room temperature for 1 h. Acetic acid (3.45 ml, 60.18 mmol) was added as a bolus followed by the portion-wise addition of sodium triacetoxyborohydride (19.1 g, 90.27 mmol). After 1.5 h, the reaction was quenched by the addition of 1 N NaOH (200 ml). The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The 10 combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as an oil (13.20 g, 86.9 %). MS (ES+) m/z 258 (M+H). Step 2: Preparation of 2-(3-(aminomethyl)phenoxy)ethanol HO O
NH
2 15 (3-((Benzylamino)methyl)phenoxy)ethanol (13.2 g) was dissolved with heating in absolute ethanol (500 mL) and ammonium formate (40.9 g, 648 mmol) was added. The mixture was sparged with N 2 for a short period before 10% Pd/C (1.5 g, 13.9 mmol) was added. The slurry was heated to reflux (55 0C to 66 *C) and stirred for 2 h. Additional catalyst (1.5 g) was added and heating at reflux (74.7 0C) was continued for 30 min. The reaction was filtered and concentrated in vacuo. The crude 20 material was chromatographed on a normal phase column eluting with 95/5/0.5, dichloromethane/methanol/NH 4 0H to afford the title compound (3.14 g). Step 3: Preparation of N-(3-(2-hydroxvethoxy)benzyl)-6-cyano-2-methylpyrimidine-4-carboxamide 0 HO ON Methyl 6-cyano-2-methylpyrimidine-4-carboxylate (prepared as described in step 4 of the 25 synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (892 mg, 5.03 mmol), 2-(3 (aminomethyl)phenoxy)ethanol (894 mg, 5.35 mmol), and triethylamine (382 mg, 3.78 mmol) were combined in dimethylacetamide (6 mL). The mixture was stirred at 80 0C for 2 h. The mixture was cooled and partitioned into ethyl acetate and water. The aqueous layer was extracted with additional 107 WO 2009/016498 PCT/IB2008/002046 ethyl acetate (15 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (dichloromethane/methanol, 100/0 - 95/5). The pure fractions were combined and concentrated to afford the title compound as an oil (950 mg, 60%). LC/MS (10%-90% CH 3
CN:H
2 0, 8 min): 2,338 min, m/z 313 (M+H). 5 Step 4: Preparation of N-(3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-l )pyrimidine-4 carboxamide O N-N, I HH HOH N -NN N-(3-(2-Hydroxyethoxy)benzyl)-6-cyano-2-methylpyrimidine-4-carboxamide (687 mg, 2.20 mmol), sodium azide (214 mg, 3.30 mmol), and zinc(II) bromide (248 mg, 1.10 mmol) were combined 10 in methanol (10 mL). The resulting mixture was stirred at 60 *C until homogeneous, then cooled to 25 0C and stirred for 18 h. The methanol was removed, the solution acidified to pH 3 (3N hydrochloric acid) and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow solid (782 mg, 100%). LC/MS (10%-90% CH 3
CN/H
2 0, 8 min): 3.58 min, m/z 356 (M+H). 15 Step 5: Preparation of N-(3-(2-hydroxvethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide !4N HO O N _NH -
'NH
2 N NN O N N-(3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (782 mg, 2.20 mmol), (trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate 20 (prepared as described in step 7 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (844 mg, 2.20 mmol), and triethylamine (267 mg, 2.64 mmol) were combined in dimethylacetamide (12 mL). The resulting mixture was stirred at 85 *C for 18 h. The mixture was partitioned into water/ethyl acetate and extracted with additional ethyl acetate (5 mL). The organic extracts were combined, dried 25 over magnesium sulfate, filtered and concentrated. Purification was accomplished by reverse phase high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil. The intermediate was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred 10 min., concentrated, and neutralized to pH 8 (NaOH). The mixture was extracted with ethyl 30 acetate (2 x 15 mL), dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (100 mg, 8%). LC/MS (10%-90% CH 3
CN/H
2 0, 6 min): 5.92 min, m/z 467 (M+H). 108 WO 2009/016498 PCT/IB2008/002046 Example 14 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-y)-2 methylpyrimidine-4-carboxamide HO 0 N N'N O N 5 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 13) (50 mg, 0.11 mmol), triethylamine (38.0 mg, 0.375 mmol) and acetyl chloride (10.1 mg, 0.129 mmol) were combined in dichloromethane (2 mL). After stirring for 18 h, the mixture was concentrated and then treated with acetonitrile (2 mL) and 2.5 N sodium hydroxide (2 mL). After 1 h, the organics were removed under a 10 nitrogen stream and the aqueous layer was adjusted to pH 6 with 10% hydrogen chloride. The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (6 mg, 11%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min): 2.45 min, m/z 509 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.41 9.48 (m, 1 H), 8.39 (s, 1 H), 7.58-7.64 (m, 1 H), 7.14 - 7.24 (m, 1 H), 6.83 - 6.94 (m, 2 H), 6.77 - 6.84 15 (m, 1 H), 5.43 - 5.55 (m, 1 H), 4.64 - 4.71 (m, 1 H), 4.45 - 4.51 (m, 2 H), 3.97 (m, 1 H), 3.62 - 3.72 (m, 2 H), 3.37 - 3.48 (m, 1 H), 2,81 (s, 3 H), 1.88 - 2.03 (m, 2 H), 1.84 (m, 2 H), 1.72 (s, 3 H), 1.63 (m, 2 H), 0.95 - 1.26 (m, 5 H). Example 15 N-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2-(((trans)-4 20 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide HO 0 N N " O N NH -'\ 0 N H N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 13) (184 mg, 0,409 mmol), triethylamine (200 pL) and methanesulfonyl chloride (46.9 mg, 0.409 mmol) were combined in 25 dichloromethane (2 mL). After stirring for 18 h, the resulting mixture was stirred at 85 *C for 18 h. The mixture was concentrated under a nitrogen stream. Purification was accomplished by high-pressure liquid chromatography. Pure fractions were combined and concentrated to afford the title compound as a white solid (6.5 mg, 2.9%). LC/MS (10%-90% CH 3
CN/H
2 0, 8 min): 4.26 min, m/z 545 (M+H). IH NMR (400 MHz, DMSO-d) 6 ppm 9.48 (s, 1 H), 8.42 (s, 1 H), 7.23 (m, 1 H), 6.93 (m, 2 H), 6.83 (m, 1 30 H), 4.77 (m, 1 H), 4.70 (d, J = 6.6 Hz, 2 H), 4.51 (d, J = 6.22 Hz, 2 H), 3.96 (t, J = 4.9 Hz, 2 H), 3.69 (d, 109 WO 2009/016498 PCT/IB2008/002046 J = 5.1 Hz, 2 H), 3.06 (m, 1 H), 2.85 (s, 3 H), 2.83 (s, 3 H), 1.90 (m, 3 H), 1.64 (m, 2 H), 1.20 (m, 4 H), 0.06 (m, 1 H). Example 16 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H 5 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide HO N HONH N OH \ /N H O N N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 13) (184 mg, 0.409 mmol), triethylamine (200 pL) and acetoxy acetyl chloride (55.9 mg, 0.409 mmol) were combined in 10 dichloromethane (4 mL). After stirring for 10 min., the mixture was concentrated then treated with acetonitrile (2 mL) and 2.5 N sodium hydroxide (2 mL). After 1 h, the organics were removed under a nitrogen stream and the aqueous layer was adjusted to pH 6 with 10% hydrogen chloride. The mixture was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (79.9 mg, 37%). LC/MS 15 (10%-90% CH 3
CN/H
2 0, 6 min): 4.00 min, m/z 525 (M+H). 1 H NMR (400 MHz, DMSO-de) 6 ppm 9.48 (s, 1 H), 8.31 (s, 1 H), 7.52 (s, 1 H), 7.38 - 6.94 (m, 4 H), 3.85 (s, 1 H), 3.72 (d, J = 11.4 Hz, 4 H), 3.47 (t, J = 11.0, 4 H), 2.60 (s, 3 H), 2.41 (d, J = 13.2, 4 H), 1.79 (m, 8 H), 0.06 (m, 1 H). Example 17 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H 20 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F HO 0 N N N H N N O / N H 0 N Step 1: Preparation of methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate 0 0 O NN N NNH Methyl 6-cyano-2-methylpyrimidine-4-carboxylate (prepared as described in step 4 of the 25 synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (5.00 g, 28.2 mmol), sodium azide (1.93 g, 29.6 mmol), 110 WO 2009/016498 PCT/IB2008/002046 and zinc bromide (6.36 g, 28.2 mmol) were suspended in methanol (28 mL). The reaction was stirred at room temperature for 16 hours. 1 N hydrochloric acid (75 mL) was added and the mixture was stirred vigorously for 1 hour. The solids were collected by vacuum filtration and rinsed with 1 N hydrochloric acid (2 x 50 mL) and water (2 x 100 mL). High vacuum drying at 40 *C provided the title 5 compound as a white solid (5.31 g, 85%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.24 min, m/z 221 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 8.38 (s, 1 H), 3.94 (s, 3 H), 2.80 (s, 3 H). Step 2: Preparation of methyl 6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxylate 0 0 N I
NH
2 N N' 10 Methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (2.00 g, 9.0 mmol), tert-butyl (trans)-4-(hydroxymethyl)cyclohexylcarbamate (2.29 g, 9.99 mmol), resin-bound triphenylphosphine (4.84 g, 10.9 mmol) and di-tert-butyl azodicarboxylate (2.3 g, 9.99 mmol) were combined in tetrahydrofuran (30 mL). The mixture was stirred at 25 0C for 18 h. The mixture was filtered and concentrated. The residue was purified by reverse phase preparative high-pressure liquid 15 chromatography. Fractions containing methyl 6-(2-((trans-4-((tert butoxycarbonyl)amino)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated. The residue was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred 10 min, concentrated, and neutralized to pH 8 (NaOH). The organic layer was 20 extracted with ethyl acetate (2 x 15 mL), dried with magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (400 mg, 7%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min): 1.704 min, m/z 332 (M+H). Step 3: Preparation of 5-aminomethyl-2-fluoro-phenol hydrobromide HO
-
NH
2 HBr 25 A mixture of 4-fluoro-3-methoxy-benzylamine hydrochloride (133 g, 0.642 mol), 48% aqueous HBr (1 L) and 30% HBr in acetic acid (1 L) was refluxed for 4 h and concentrated under vacuum. Ethanol was added to the residue and evaporated to remove last remaining water. The crystalline residue obtained was dissolved in a small amount of ethanol and ethyl ether was slowly added. A heavy crystalline suspension formed and was filtered, washed with ethyl ether and dried in vacuum to 30 afford the title compound (147 g, 95.4%). 111 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of tert-butvl 4-fluoro-3-hydroxybenzylcarbamate 0 HO O N H Triethylamine (13.7 g, 0.135 mol) and di-tert-butyl dicarbonate (29.5 g, 0.135 mol) were added to a solution of 5-aminomethyl-2-fluorophenol hydrobromide (30 g, 0.135 mol) in dichloromethane (200 5 mL) at ice bath temperature. The reaction mixture was stirred overnight at room temperature, diluted with water and adjusted to pH-5 with acetic acid. The organic layer was separated, washed with water and concentrated under vacuum to afford the title compound as a clear viscous oil (31.5 g, 96%). Step 5: tert-butyl 4-fluoro-3-(2-hydroxvethoxy)benzylcarbamate 0 HO N O IH F 10 To a mixture of tert-butyl 4-fluoro-3-hydroxybenzylcarbamate (31.5 g, 0.13 mol) in dimethylsulfoxide (300 mL) was added KOH (15.75 g), KI (0.3 g) and bromoethanol (19.6 g, 0.157 mol). The mixture was stirred for 5 days until no starting material remained. The mixture was diluted with excess dichloromethane and washed with water. The organic solution was concentrated and the crude product purified by silica gel column chromatography (0-80% ethyl acetate in hexane) to afford 15 the desired tert-butyl 4-fluoro-3-(2-hydroxyethoxy)benzylcarbamate as an oil (14 g, 40%). Step 6: Preparation of 2-(5-aminomethyl-2-fluorophenoxy)ethanol hydrochloride HO O NH 2 HCI F tert-Butyl 4-fluoro-3-(2-hydroxyethoxy)benzylcarbamate (14 g, 0.05 mol) was dissolved in excess of 4N hydrochloric acid in dioxane (125 ml) and stirred for 5 h at room temperature. The 20 resulting solid was diluted with an additional amount of dioxane and then filtered, washed with cold dioxane and dried in vacuo to afford the title compound as the hydrochloride salt (8.5 g, 78%). MS (ES+) m/z 186 (M+H). Elemental analysis found: C, 48.25; H, 6.09; N, 6.45. Step 7: Preparation of N-(4-fluoro-3-(2-hydroxyethoxv)benzvl)-6-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methyl pyrimidine-4-carboxamide F HO 0 N N NH N N H 25 Methyl 6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y)-2-methylpyrimidine-4 carboxylate (134 mg, 0.404 mmol), acetyl chloride (104 mg, 1.33 mmol) and triethylamine (200 pL) 112 WO 2009/016498 PCT/IB2008/002046 were combined in dichloromethane (2 mL). The resulting mixture was stirred at 25 0C for 30 min. The dichloromethane was removed under nitrogen stream. The residue was dissolved in dimethylacetamide (2 mL) and 2-(5-(aminomethyl)-2-fluorophenoxy)ethano hydrochloride (178 mg, 0.808 mmol) and triethylamine (200 pL) were added. The mixture was stirred at 25 C for 18 h. 5 Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 min). The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried (magnesium sulfate), and concentrated to an oil that solidified under reduced pressure to afford the title compound as a white solid (48.5 mg, 23%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min) 2.53 min, m/z 527 (M+H). 1H NMR (400 MHz, DMSO-d) 6 ppm 9.47 (s, 1 H), 8.40 (s, 1 H), 10 7.61 (d, J = 8.05, 1 H), 7.18 (m, 2 H), 6.90 (m, 1 H), 4.81 (t, J = 5.68, 5.86, 1 H), 4.67 (d, J = 7.32, 2 H), 4.47 (d, J = 6.59, 2 H), 4.01 (m, 2 H), 3.71 (m, 2 H), 3.45 (m, 1 H), 2.81 (s, 3 H), 1.97 (m, 1 H), 1,78 (m, 2 H), 1.73 (s, 3 H), 1.58 (m, 2 H), 1.14 (m, 4 H). Example 18 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2-(((trans)-4 15 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide F HO 0 N N NH N \ N 0 N Methyl 6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxylate (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 20 methylpyrimidine-4-carboxamide, Example 17) (134 mg, 0.404 mmol), methanesulfonyl chloride (152 mg, 1.33 mmol) and triethylamine (200 pL) were combined in dichloromethane (2 mL). The resulting mixture was stirred at 25 0C for 30 min. The dichloromethane was removed under nitrogen stream. The residue was dissolved in dimethylacetamide (2 mL) and 2-(5-(aminomethyl)-2 fluorophenoxy)ethanol (prepared as described in steps 3 - 6 of the synthesis of N-(4-fluoro-3-(2 25 hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexy)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 17) (178 mg, 0.808 mmol) and triethylamine (200 pL) were added. The mixture was stirred at 25 *C for 18 h. Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 min). The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and 30 concentrated to an oil that solidified under reduced pressure to afford the title compound as an white solid (45.3 mg, 20%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min) 2.64 min, m/z 563 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.47 (m, 1 H), 8.40 (s, 1 H), 7.13 (m, 2 H), 6.90 (m, 2 H), 4.79 (m, 1 H), 4.68 (m, 2 H), 4.47 (m, 2 H), 4.03 (m, 2 H), 3.70 (m, 2 H), 3.05 (m, 1 H), 2.86 (s, 3 H), 2.81 (s, 3 H), 1.93 (m, 3 H), 1.61 (m, 2 H), 1.18 (m, 4 H). 113 WO 2009/016498 PCT/IB2008/002046 Example 19 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide F HO 0 N'NN NH N OH SN H 0 N 5 Methyl 6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y)-2-methylpyrimidine-4 carboxylate (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexy)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 17) (134 mg, 0.404 mmol), acetoxy acetyl chloride (181 mg, 1.33 mmol) and triethylamine (200 pL) were combined in dichloromethane (2mL). The resulting 10 mixture was stirred at 25 0C for 30 min. The dichloromethane was removed under nitrogen stream. The residue was dissolved in dimethylacetamide (2 mL) and (2-(5-(aminomethyl)-2 fluorophenoxy)ethanol (prepared as described in steps 3 - 6 of the synthesis of N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexy)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 17) (178 mg, 0.808 mmol) and triethylamine (200 pL) were 15 added. The mixture was stirred at 25 *C for 18 h. Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 min). The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated. The residue was dissolved in acetonitrile (4.5 mL) and treated with 2.5N NaOH (2.5 mL). The acetonitrile was removed in vacuo and the aqueous layer was adjusted to pH 6 with 10% 20 hydrochloric acid. The mixture was extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil the solidified under reduced pressure to give the title compound as an white solid (52.2 mg, 24%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min): 2.43 min, m/z 543 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.47 (s, 1 H), 8.40 (s, 1 H), 7.35 (m, 1 H), 7.09 - 7.18 (m, 2 H), 6.90 (m, 1 H), 5.30 (m, 1 H), 4.81 (m, 1 H), 4.68 (d, J = 7.32, 2 H), 4.47 (d, J = 6.59, 2 H), 4.02 (m, 2 H), 25 3.70 (m, 4 H), 3.53 (m, 1 H), 2.81 (s, 3 H),1.97 (m, 1 H), 1.72 (m, 2 H), 1.62 (m, 2 H), 1.15 - 1.28 (m, 4 H). Example 20 trans-Methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate F 0 O O -O / N N 0 O -N N'N \, 30 114 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of trans-methyl 4-((methylsulfonyloxy'lmethyl)cyclohexanecarboxylate 0 -S-O 00 0 Triethylamine (6.46 g, 63.9 mmol) was added to a solution of trans-methyl 4 (hydroxymethyl)cyclohexanecarboxylate (10.0 g, 58.1 mmol) in dichloromethane (100 mL). Methane 5 sulfonylchloride (7.98 g, 69.7 mmol) was added drop-wise and then the mixture was stirred at room temperature for 2 days. The mixture was diluted with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The resulting oil crystallized upon addition of petroleum ether and was filtered to afford the title compound (14.0 g). Step 2: Preparation of trans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin 10 4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate F 0 - HN 00 -O N N O N N' 0 trans-Methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (65 mg, 0.26 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (60 mg, 0.17 mmol) and triethylamine (34 mg, 0.34 mmol) in anhydrous 15 dimethylacetamide (0.3 mL). The mixture was stirred at 80 - 90 *C in a capped vial overnight. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (43 mg). Example 21 trans-4-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-y)-2H-tetrazol-2 20 yl)methyl)cyclohexanecarboxylic acid F NOO -_P HN 0o -O N N N N I OH />:::::N N'N ( Sodium hydroxide (2 pellets) were added to a mixture of trans-methyl 4-((5-(6-((4-fluoro-3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (43 mg) in tetrahydrofuran (0.4 mL) and water (0.4 mL). The mixture was stirred at room temperature 25 overnight. The reaction mixture was acidified with trifluoroacetic acid and the product was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (28 mg). MS (ES+) m/z 484 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.51 (1 H, t, J=6.0 Hz), 8.42 (1 H, s), 7.11 - 7.22 (1 H, m), 6.92 (1 H, br. s.), 4.70 (3 H, d, J=6.6 Hz), 4.51 (3 H, d, J=5.9 Hz), 3.82 (3 H, 115 WO 2009/016498 PCT/IB2008/002046 s), 2.83 (3 H, s), 2.14 (1 H, br. s.), 1.99 (1 H, br. s.), 1.90 (2 H, br. s.), 1.64 (2 H, br. s.), 1.30 (3 H, d, J=12.8 Hz), 1.08 - 1.19 (2 H, m). Example 22 (trans)-Methyl 4-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 5 yl)methyl)cyclohexanecarboxylate 5N N -N / \, -' N N O N N' trans-Methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (prepared as described in step 1 of the synthesis of trans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 20) (56 mg, 0.22 10 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (50 mg, 0.15 mmol) and triethylamine (56 mg, 0.22 mmol) in anhydrous dimethylacetamide (0.3 mL). The mixture was stirred at 80 - 90 0C in a capped vial overnight. The reaction mixture was purified by 15 reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (37 mg). Example 23 (trans)-4-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid 0 N N -O N N : N N NN\I, OH =N N'N ,\,0 20 Sodium hydroxide (2 pellets) was added to mixture of (trans)-methyl 4-((5-(6-((3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 22) in tetrahydrofuran (0.4 mL) and water (0.4 mL). The mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile). The resulting residue was 25 slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as an off-white solid (19 mg). MS (ES+) m/z 466 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.49 (1 H, t, J=6.2 Hz), 8.41 (1H,s), 7.24 (1 H, t, J=8.1 Hz), 6.93 (2 H, br. s.), 6.83 (1 H, d, J=7.7 Hz), 4.70 (2 H, d, J=7.0 Hz), 4.51 (3 H, d, J=6.2 Hz), 3.74 (3 H, s), 2.83 (3 H, s), 2.14 (1 H, br. s.), 2.01 (1 H, br. s.), 1.91 (2 H, d, J=12,1 Hz), 1,64 (2 H, br. s.), 1.30 (3 H, d, J=12.4 Hz), 1.14 (2 H, t, J=11.3 Hz). 116 WO 2009/016498 PCT/IB2008/002046 Example 24 N-(3-Methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 0 NN'N NH CN \ /N 0 N 5 Step 1: Preparation of 1,4-dioxa-spirof4.51decane-8-carbonitrile CN To a cold (-10 *C) suspension of 1,4-dioxa-spiro[4.5]decan-8-one (123.0 g, 0.79 mol) and tosyl-methyl-isocyanide (200.0 g, 1.024 mol) in DMF (2.2 L) and ethanol (85 mL), was added potassium t-butoxide (210,0 g, 1.87 mol) portion wise over a period of 2 h, and the temperature was 10 maintained below -5 *C. After complete addition, the mixture was brought to 0 *C and stirred another 1 h at 0 *C followed by room temperature for another 2.5 h. The reaction mixture was diluted with ethyl acetate (3.5 L) and water (3.5 L). The mixture was stirred for 1 h. The organic layer was separated and washed with water (3 x 1.5 L) followed by brine solution (1.5 L), dried over anhydrous sodium sulfate, and concentrated to afford the title compound as an oil (99 g, 75 %). 15 Step 2: Preparation of 4-oxocyclohexanecarbonitrile O CN To a stirred solution of 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (100 g, 0.60 mol) in tetrahydrofuran (1.0 L) was added 2N hydrochloric acid (1.0 L) at room temperature and the mixture was stirred for 24 h. The reaction mixture was diluted with ethyl acetate (1.0 L). The organic layer was 20 separated and the aqueous layer was extracted with ethyl acetate (2 x 700 mL). The combined organic layer was washed with water (1.5 L) followed by brine (1.0 L), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by flash column chromatography over silica gel (230-400 mesh) eluting with 20% ethyl acetate in hexane to afford the title compound (50 g, 67 %). Step 3: Preparation of 4-(methoxymethylene)cvclohexanecarbonitrile MeO 25 MeO CN To a cold (-30 *C) suspension of methoxy methyl triphenylphosphonium chloride (84 g, 163 mmol) in dry tetrahydrofuran (300 mL) was added drop-wise 1.6 M n-butyllithium (153 mL, 243.6 mmol) maintaining the temperature at -25 *C to -30 *C. After complete addition, the mixture was allowed to stir for 1 h at -20 *C, A solution of 4-oxocyclohexanecarbonitrile (20 g, 162.4 mmol) in 30 tetrahydrofuran (150 mL) was added drop-wise at -20 * and allowed to stir for 2 h at the same temperature. Hexane (200 mL) was added, and the mixture was filtered, The filtrate was concentrated 117 WO 2009/016498 PCT/IB2008/002046 under reduced pressure and the crude material was purified by flash column chromatography over silica gel (230-400 mesh) eluting with 10% ethyl acetate in hexane to afford the title compound (9 g, 36%). Step 4: Preparation of trans-4-formvlcyclohexanecarbonitrile H CN 5 0 A mixture of 4-(methoxymethylene)cyclohexanecarbonitrile (9 g, 59.5 mmol) and tetrahydrofuran /2N hydrochloric acid (4:1, 400 mL v/v) was heated to reflux for 30 minutes. The reaction mixture was poured into water (300 mL) cold water and extracted with diethyl ether (3 x 300 mL). The combined organic layer was washed with water (400 mL), dried over anhydrous sodium 10 sulfate and concentrated. Recrystallization from hexane afforded the title compound (2.1 g, 25 %). Step 5: Preparation of trans-4-(hydroxymethyl)cyclohexanecarbonitrile HO A suspension of 600 mg (189.15 mmol) of sodium borohydride in methanol/diethyl ether (9:1, 70 mL v/v) was treated drop-wise with a solution of trans-4-formylcyclohexanecarbonitrile (2 g, 14.6 15 mmol) in methanol/diethyl ether (9/1, 30 mL v/v) within 10 minutes at 0 *C. The reaction mixture was allowed to stir for 2 h at 10 0C, treated with 2N hydrochloric acid (35 mL) under ice-water cold condition, and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil (1.45 g, 71 %). MS (ES+) m/z 162 (M+Na). 20 Step 6: Preparation of (trans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate 0 / -O O CN p-Toluene sulfonyl chloride (2.15 g, 11.3 mmol) was added portion-wise over 30 min to a solution of trans-4-(hydroxymethyl)cyclohexanecarbonitrile (1.57 g, 11.3 mmol) in anhydrous pyridine (10 mL) at room temperature. The reaction mixture was stirred for 4 h and then water (40 mL) was 25 added drop-wise with ice bath cooling. The mixture was extracted with dichloromethane. The organic layer was washed with 3 M hydrochloric acid, dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as a white solid (2.4 g). 118 WO 2009/016498 PCT/IB2008/002046 Step 7: Preparation of N-(3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexVl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide 0 N' N N CNN 0< NH N ON O N 0 N (trans-4-Cyanocyclohexyl)methyl 4-methylbenzenesulfonate (232 mg, 0.79 mmol) was added 5 to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (200 mg, 0.61 mmol) and triethylamine (186 mg, 1.8 mmol) in anhydrous dimethylacetamide (0.3 mL). The reaction was stirred overnight at 85 *C in a capped vial. The reaction mixture was purified by reverse 10 phase preparative HPLC (water/acetonitrile), Fractions containing product were neutralized by passing through a small carbonate resin column and concentrated. The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (64 mg). MS (ES+) m/z 447 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.48 (1 H, t, J=6.2 Hz), 8.41 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.93 (2 H, br. s.), 6.83 (1 H, d, J=8.1 Hz), 4.71 (2 H, d, J=7.0 Hz), 15 4.51 (2 H, d, J=6.2 Hz), 3.74 (3 H, s), 2.83 (3 H, s), 2.63 (1 H, br. s.), 2.08 (1 H, br. s.), 2.02 (2 H, d, J=1 1.3 Hz), 1.65 (3 H, d, J=1 1.0 Hz), 1.51 (2 H, d, J=12.8 Hz), 1.15 (2 H, t, J=1 1.3 Hz). Example 25 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazo-5-yl)-2 methylpyrimidine-4-carboxamide F 0 N N0 NH N CN o N 20 (trans-4-Cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 24) (214 mg, 0.73 mmol) was added to a solution of N-(4 fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as 25 described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (170 mg, 0.495 mol) and triethylamine (148 mg, 1.4 mmol) in anhydrous dimethylacetamide (0.4 mL). The mixture was stirred overnight at 85 *C in a capped vial. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing 30 through a small carbonate resin column and concentrated. The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white 119 WO 2009/016498 PCT/IB2008/002046 solid (65 mg). MS (ES+) m/z 465 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.50 (1 H, t, J=6.4 Hz), 8.42 (1 H, s), 7.19 (1 H, d, J=8.4 Hz), 7.14 (1 H, dd, J=11.5, 8.6 Hz), 6.91 (1 H, br. s.), 4.71 (2 H, d, J=7.0 Hz), 4.51 (2 H, d, J=6.2 Hz), 3.83 (3 H, s), 2.83 (3 H, s), 2.63 (1 H, br. s.), 2.01 (3 H, br. s.), 1.63 (3 H, br. s.), 1.50 (2 H, br. s.), 1.08 - 1.19 (2 H, m). 5 Example 26 N-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazo-5-yl)-2 methylpyrimidine-4-carboxamide HO 0 N N _NH - O O N N-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide 10 (prepared as described in steps 1 - 4 of the synthesis of N-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 13) (180 mg, 0.614 mmol), (trans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in steps 1 - 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 24) (150 mg, 0.423 mmol ), and 15 triethylamine (400 pL) were combined in dimethylacetamide (100 pL). The resulting mixture was stirred at 85 *C for 18 h. The mixture was concentrated under a nitrogen stream. Purification was accomplished by reverse phase preparative high-pressure liquid chromatography. Pure fractions were combined and concentrated to afford the title compound as a white solid (36.6 mg, 12%). MS (ES+) m/z 477 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.48 (m, 1 H), 8.30 (s, 1 H), 7.24 (m, 1 H), 6.91 20 (m, 2 H), 6.79 (m, 1 H), 4.81 (m, 1 H), 4.71 (m , 2 H), 4.52 (m, 2 H), 3.96 (m, 2 H), 3.61 (m, 2 H), 2.80 (s, 3 H), 2.61 (m, 1 H), 2.40 (m, 1 H), 2.01 (m, 4 H), 1.62 (m, 2 H), 1.44 (m, 2 H), 1.05 (m, 2 H). Example 27 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide F HO 0 -N N, N N H C N N 0 N 1 25 120 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of N-(4-fluoro-3-(2-hydroxvethoxy)benzyl)-6-cyano-2-methylpyrimidine-4 carboxamide HO N Methyl 6-cyano-2-methylpyrimidine-4-carboxylate (prepared as described in step 4 of the 5 synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (5.20 g, 29.0 mmol), 2-(5-(aminomethyl)-2 fluorophenoxy)ethanol hydrochloride (prepared as described in steps 3 - 6 of the synthesis of N-(4 fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 17) (8.30 g, 32.3 mmol), and triethylamine (5.94 g, 58.7 10 mmol) were combined in dimethylacetamide (50 mL). The mixture was stirred at 80 *C for 2 h. The mixture was cooled and poured into 1N hydrochloric acid (50 mL) and was extracted with ethyl acetate (3 x 30 mL). The combined organic layers dried over magnesium sulfate, filtered and concentrated to a crude oil. The product was triturated with ethyl acetate to afford the title compound as a solid (1.5 g, 15%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min): 2.437 min, m/z 331 (M+H). 15 Step 2: Preparation of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-vl)pyrimidine 4-carboxamide 0 N'N H O N NN H F H N N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyrimidine-4-carboxamide (7.93 g, 24.0 mmol), sodium azide (2.34 g, 36.0 mmol), and zinc(II) bromide (2.70 g, 12.0 mmol) were 20 combined in methanol (50 mL). The resulting mixture was stirred at 25 *C for 18 h. The methanol was removed and the residue was acidified to pH 3 (3N hydrochloric acid) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an off-white solid (4.25g, 47%). LC/MS (10%-90%
CH
3
CN/H
2 0, 4 min): 2.274 min, m/z 374 (M+H). 121 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(4-fluoro-3-(2-hydroxyethoxy)benzvl)-6-(2-(((trans-4-cyanocyclohexvl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F HO 0 NN NH CN N O N (trans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in steps 1 5 - 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide, Example 24) (114 mg, 0.389 mmol ) was added to a solution of N (4-fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (100 mg, 0.268 mmol) and triethylamine (162 mg, 1.6 mmol) in anhydrous dimethylacetamide (0.2 mL). The mixture was stirred overnight at 85 0C in a capped vial. The reaction mixture was purified by reverse 10 phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a small carbonate resin column and concentrated. The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (46 mg). MS (ES+) m/z 495 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.63 (1 H, s), 7.53 7.57 (1 H, m), 7.40 - 7.51 (3 H, m), 7.34 (2 H, d, J=6.2 Hz), 7.25 (1 H, br. s.), 7.14 (2 H, br. s.), 7.03 (1 15 H, br. s.), 3.96 (1 H, s), 3.85 (4 H, d, J=11.7 Hz), 3.58 (4 H, t, J=10.8 Hz), 2.55 - 2.66 (3 H, m), 1.85 1.96 (3 H, m). Example 28 N-(3-Methoxybenzyl)-6-(2-(((trans)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide 0INN N " N N OH NH -N -OH ON 20 Step 1: Preparation of 1,4-dioxaspiro[4 5]dec-8-vlmethyl 4-methylbenzenesulfonate 0 O O p-Toluene sulfonylchloride (4.43 g, 23.24 mmol) was added portion-wise over 20 min to a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethanol (Bioorg. Med. Chem. 2005, 13, 6309-6323) (4.0 g, 25 23.0 mmol) in anhydrous pyridine (30 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0 *C and water (100 mL) was added drop-wise maintaining the temperature below 20 *C. The mixture was extracted with dichloromethane. The organic layer was 122 WO 2009/016498 PCT/IB2008/002046 washed with water (4x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as a clear oil (5.7 g). Step 2: Preparation of 6-(2-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2H-tetrazol-5-vl)-N-(3-methoxvbenzvi) 2-methylpVrimidine-4-carboxamide o N'N / O-Z H N 0 NH O N 1 o N 5O N 1 ,4-Dioxaspiro[4.5]dec-8-ylmethyl 4-methylbenzenesulfonate (552 mg, 1.69 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (550 mg, 10 1.69 mmol) and triethylamine (171 mg, 1.7 mmol) in anhydrous dimethylacetamide (0.5 mL). The mixture was stirred overnight at 85 *C in a capped vial. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (271 mg). Step 3: Preparation of N-(3-methoxybenzvl)-2-methyl-6-(2-((4-oxocyclohexvl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide o NN S /N o N 15 6-(2-(1,4-Dioxaspiro[4.5]dec-8-ylmethyl)-2H-tetrazol-5-yI)-N-(3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide (271 mg) was dissolved in tetrahydrofuran (3 mL) and 96% formic acid (4 mL) was added. The mixture was stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and the residue was dissolved in dichloromethane. The mixture 20 was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound (218 mg) Step 4: Preparation of N-(3-methoxybenzvl)-2-methyl-6-(2-(1-oxaspiro[2.5]oct-6-vlmethyl)-2H-tetrazol 5-yl)pvrimidine-4-carboxamide N N O S\ / N 0 N 25 A solution of N-(3-methoxybenzyl)-2-methyl-6-(2-((4-oxocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide (218 mg) in anhydrous dimethylsulfoxide (3 mL) was added to a solid mixture of trimethylsulfoxonium iodide (223 mg, 1.0 mmol) and potassium t-butoxide(1 13 mg, 1.0 123 WO 2009/016498 PCT/IB2008/002046 mmol), The mixture was stirred at room temperature for 40 min. Water (15 mL) was added and the resulting slurry was stirred an additional 20 min. The precipitate was filtered, washed with water, and dried under vacuum to afford the title compound (163 mg). Step 5: Preparation of N-(3-methoxybenzyl)-6-(2-(((trans)-4-hydroxy-4 5 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide N o N N ' H N NOH O N Perchloric acid (70%, 0.3 mL) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2 (1 -oxaspiro[2.5]oct-6-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (163 mg) in a mixture of tetrahydrofuran (3 mL) and water (1 mL). The resulting slurry was warmed to afford a solution and the 10 mixture was stirred at room temperature for 3.5 h, The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the first eluting product were neutralized by passing through a carbonate resin column and concentrated. The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (35 mg). MS (ES+) m/z 468 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.48 (1 H, t, J=6.2 Hz), 15 8.42 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.90 - 6.95 (2 H, m), 6.83 (1 H, d, J=8.4 Hz), 4.75 (2 H, d, J=7.3 Hz), 4.51 (2 H, d, J=6.2 Hz), 4.32 (1 H, t, J=5.9 Hz), 3.99 (1 H, s), 3.74 (3 H, s), 2.83 (3 H, s), 2.15 (1 H, br. s.), 1.71 (2 H, d, J=10.2 Hz), 1.60 (2 H, d, J=10.2 Hz), 1.17 (3 H, d, J=9.9 Hz), 1.22 (3 H, d, J=12.8 Hz). Example 29 20 N-(3-Methoxybenzyl)-6-(2-(((cis)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide 0I NN " NN OH NH ~ N OH O N Isolation of the second eluting product by reverse phase preparative HPLC from the reaction mixture described in Example 28 afforded the title compound as a white solid (19 mg). MS (ES+) m/z 25 468 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.47 (1 H, t, J=6.2 Hz), 8.41 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.90 - 6.95 (2 H, m), 6.83 (1 H, d, J=8.1 Hz), 4.69 (2 H, d, J=7.0 Hz), 4.51 (2 H, d, J=6.6 Hz), 4.41 (1 H, t, J=5.7 Hz), 3.82 (1 H, s), 3.74 (3 H, s), 3.13 (2 H, d, J=5.9 Hz), 2.83 (3 H, s), 1.95 (1 H, br. s.), 1.37 (3 H, d, J=9.2 Hz), 1.43 (5 H, t, J=13.0 Hz), 1.33 (1 H, br. s.). 124 WO 2009/016498 PCT/IB2008/002046 Example 30 N-(3-chloro-4-fluorobenzyl)-6-(2-((trans-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F Cl N NOH -OH 0 N 5 Step 1: Preparation of (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate 0 o O Formic acid (8 mL) was added to a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethyl 4 methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-6 (2-(((trans)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-y)-2-methylpyrimidine-4 10 carboxamide, Example 28) (1.0 g, 3.0 mmol) in tetrahydrofuran (5 mL). The reaction was stirred at room temperature overnight, and then solvent was removed under a stream of nitrogen. The residue was dissolved in dichloromethane, The organic layer was washed with water (1x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as an oil (852 mg). Step 2: Preparation of 1-oxaspiro[2.5]oct-6-vlmethVl 4-methylbenzenesulfonate 0 15 A solution of (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate (852 mg) in anhydrous dimethylsulfoxide (11 mL) was added in one portion to a mixture of trimethylsulfoxonium iodide (1.32 g, 6.0 mmol) and potassium t-butoxide (673 mg, 6.0 mmol). The mixture was stirred at room temperature for 1 h and then water (50 mL) was added. The reaction mixture was extracted with ethyl 20 ether (3x). The combined organic layers were washed with water (4x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as an oil (621 mg) consisting of cis and trans isomers. Step 3: Preparation of (trans-4-hydroxy-4-(hydroxymethvl)cvclohexvl)methyl 4 methylbenzenesulfonate 0 S0 25 \ OH Perchloric acid (0.5 mL) was added to a solution of 1-oxaspiro[2.5]oct-6-ylmethyl 4 methylbenzenesulfonate (621 mg) in a mixture of tetrahydrofuran (4 mL) and water (2 mL). The 125 WO 2009/016498 PCT/IB2008/002046 mixture was stirred for 2 hours. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) afforded the title compound as a clear oil (105 mg), Step 4: Preparation of N-(3-chloro-4-fluorobenzyl)-6-(2-((trans-4-hydroxy-4 (hydroxymethvl)cvclohexyl)methyl)-2H-tetrazol-5-yl)-2-methvlpVrimidine-4-carboxamide F N0 -OH NHI N OH 5 0 N trans-(4-Hydroxy-4-(hydroxymethyl)cyclohexyl)methy 4-methylbenzenesulfonate (100 mg, 0.318 mmol) was added to a solution of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5 yl)pyrimidine-4-carboxamide (88 mg, 0.25 mmol) and triethylamine (140 mg, 1.38 mmol) in anhydrous dimethylacetamide (0.3 mL). The mixture was stirred overnight at 85 0C in a capped vial. The reaction 10 mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a carbonate resin column and concentrated. The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (35 mg). MS (ES+) m/z 490 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.61 (1 H, t, J=6.2 Hz), 8.41 (1 H, s), 7.57 (1 H, d, J=7.0 Hz), 7.37 (2 H, d, J=7.7 Hz), 4.75 (2 H, 15 d, J=7.7 Hz), 4.52 (2 H, d, J=6.2 Hz), 4.33 (1 H, t, J=5.7 Hz), 4.00 (1 H, s), 3.30 (1 H, s), 2.83 (3 H, s), 2.15 (1 H, br. s.), 1.71 (2 H, d, J=8.4 Hz), 1.60 (2 H, d, J=10.2 Hz), 1.17 (2 H, d, J=9.5 Hz), 1.22 (3 H, d, J=12.8 Hz). Example 31 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl) 20 2-methylpyrimidine-4-carboxamide F N -O N N N N NH 2 Step 1: Preparation of terl-butyl rac-(1R*,3S*)-3-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-vl)methyl)cyclopentylcarbamate F- HN0 -0 NzZN 0 F N N 25 In a 20 ml scintillation vial with a magnetic stir bar at room temperature, N-(4-fluoro-3 methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 126 WO 2009/016498 PCT/IB2008/002046 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (227 mg, 0.66 mmol) was combined with tert butyl rac-(1S*,3R*)-3-(hydroxymethyl)cyclopentylcarbamate (193 mg, 0.90 mmol), polymer supported triphenylphosphine (247 mg, 0.531 mmol), and anhydrous tetrahydrofuran (15 ml) and stirred for 1 5 hour. The mixture was cooled to -10 *C. Di-tert-butyl azodicarboxylate (174 mg, 0.76 mmol) was added. After 2 h, the reaction mixture was allowed to warm to room temperature and continue to stir for 14 hours. The reaction mixture was concentrated, dissolved in acetonitrile and water and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30%-80% acetonitrile, 10 min hold, 45 min run, 10 min hold). The desired product fractions were collected, 10 combine and concentrated under vacuum to afford the title compound as a white solid (80 mg). 'H NMR (400 MHz, CDC1) 6 ppm 1.17 - 1.29 (m, 1 H), 1.41 (s, 9 H), 1.44 - 1.59 (m, 1 H), 1.61 (s, 3 H), 1.70 (br. s., 1 H), 2.01 (br. s., 1 H), 2.16 (br. s., 1 H), 2.59 (d, J=7.52 Hz, 1 H), 2.83 (s, 1 H), 3.88 (s, 3 H), 4.50 (br. s., 1 H), 4.63 (d, J=6.18 Hz, 1 H), 4.97 (dd, J=7.52, 3.22 Hz, 2 H), 6.84 - 6.92 (m, 1 H), 6.98 (dd, J=8.06, 1.88 Hz, 1 H), 7.05 (dd, J=11.01, 8.32 Hz, 1 H), 8.18 - 8.30 (m, 1 H), 8.91 (s, 1 H). 15 LC/MS (5%-95%, CH 3
CN/H
2 0,, 5 min.) 3.428 min, m/z 541 (M+H). Step 2: Preparation of rac-N-(4-fluoro-3-methoxybenzyl)-6-(2-(((1S*,3R*)-3-aminocyclopentyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N -O N -oN X ZZ N N.N NH 2 Trifluoroacetic acid (21.1 mg, 0.19 mmol) was added to a solution of tert-butyl rac-(1R*,3S*)-3 20 ((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)cyclopentylcarbamate (80 mg, 0.15 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to afford the trifluoroacetic acid salt of the title compound (80 mg). LC/MS (5%-95%, CH 3
CN/H
2 0, 5 min.) 2.383 min, m/z 441 (M+H). 25 Example 32 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide F N NHNN 0 0 Nzz N 0 N N. N H In a 2 dram vial with a magnetic stir bar at room temperature, rac-N-(4-fluoro-3 30 methoxybenzyl)-6-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide trifluoroacetic acid salt (prepared as described in Example 31) (40 mg, 0.7 mmol) was 127 WO 2009/016498 PCT/IB2008/002046 dissolved in N,N-dimethyl formamide (2.0 ml). Acetic anhydride( 9.21 mg, 0.09 mmol) and N,N diisopropylethylamine (37.3 mg, 0.28 mmol) were added. The reaction mixture was concentrated, dissolved in acetonitrile and water and chromatographed by reversed phase preparative HPLC (30% 70% acetonitrile/water, 10 min hold, 45 min run, 10 min hold). Fractions containing the desired product 5 were collected and concentrated under vacuum to afford the title compound as a white solid (10.0 mg). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.16 - 1.27 (m, 2 H), 1.43 - 1.55 (m, 2 H), 1.76 (s, 5 H), 2.01 (d, J=12.8 Hz, 1 H), 2.83 (s, 3 H), 3.82 (s, 3 H), 4.00 (d, J=7.3 Hz, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.82 (br. s., 1 H), 4.83 (d, J=2.2 Hz, 1 H), 6.92 (d, J=4.4 Hz, 1 H), 7.16 (td, J=12.0, 8.6 Hz, 2 H), 7.84 (br. s., 1 H), 8.42 (s, 1 H), 9.48 - 9.54 (m, 1 H). LC/MS (5%-95%, CH 3
CN/H
2 0, 5 min.) 2.842 min, m/z 10 441 (M+H). Example 33 (+)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide F - /HN 0 N N-N N H 15 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 32) was separated by supercritical fluid chiral chromatography (Chiralcel AD-H column, 30 x 250 mm, 20% 2 propanol, 70 mL/min), Isolation of the first eluting isomer afforded the title compound (49.4 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.813 min., m/z 483 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 20 ppm 1.21 (br. s., 1 H), 1.47 (d, J=5.49 Hz, 1 H), 1.70 (br. s., 1 H), 1.76 (s, 3 H), 2.01 (br. s., 1 H), 2.61 (br. s., 1 H), 2.82 (s, 2 H), 3.37 (s, 9 H), 3.82 (s, 2 H), 4.00 (br. s., 1 H), 4.50 (d, J=6.22 Hz, 1 H), 4.81 (dd, J=7.14, 2.01 Hz, 1 H), 6.90 (br. s., 1 H), 7.16 (d, J=2.20 Hz, 1 H), 7.85 (br. s., 1 H), 9.51 (s, 1 H). [0]D 2 1C = +3.7 0 (c = 0.7, dichloromethane) Example 34 25 (-)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 R*,3S*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide F N -O N N , O / -N N'N HN rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 32) was 30 separated by supercritical fluid chiral chromatography (Chiralcel AD-H column, 30 x 250 mm, 20% 2 propanol, 70 mL/min). Isolation of the second eluting isomer afforded the title compound (44.8 mg). 128 WO 2009/016498 PCT/IB2008/002046 LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.813 min., m/z 483 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.21 (br. s., 1 H), 1.47 (d, J=5.89 Hz, 1 H), 1.70 (br. s., 1 H), 1.76 (s, 3 H), 2.01 (br. s., 1 H), 2.61 (br. s., 1 H), 2.83 (s, 2 H), 3.37 (s, 9 H), 3.82 (s, 2 H), 4.10 (br. s., 1 H), 4.51 (d, J=6.62 Hz, 1 H), 4.91 (dd, J=7.54, 2.01 Hz, 1 H), 6.90 (br. s., 1 H), 7.18 (d, J=2.50 Hz, 1 H), 7.86 (br. s., 1 H), 9.53 (s, 1 H). 5 [a] 0 2rc = 4.6*.(c = 0.7, dichloromethane) Example 35 rac-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3R*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyri midfine-4-carboxamide F N N NN N 0 H 10 In a 2 dram vial with a magnetic stir bar at room temperature, rac-N-(4-fluoro-3 methoxybenzyl)-6-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine- 4 carboxamide trifluoroacetic acid salt (prepared as described in Example 31) (40 mg, 0.7 mmol) was dissolved in N,N-dimethyl formamide (2,0 ml). N,N-Diisopropylethylamine (28.0 mg, 0.216 mmol) and methane sulfonyl chloride (10.3 mg, 0.09 mmol) was added and the mixture was stirred for 1 h. The 15 reaction mixture was concentrated, dissolved in acetonitrile and water and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30%-70% acetonitrile, 10 min hold, 45 min run, 10 min hold) Fractions containing the desired product were collect and concentrated under vacuum to afford the title compound as a white solid (10.4 mg). LC/MS (5%-95%, CH 3
CN/H
2 0, 5 min.) 2.925 min, m/z 519 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.48 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 20 7.06 - 7.19 (m, 3 H), 6.86 - 6.91 (m, 1 H), 4.80 (d, J=7.3 Hz, 2 H), 4.48 (d, J=6.2 Hz, 2 H), 3.80 (s, 3 H), 3.59 - 3.69 (m, 1 H), 2.85 (s, 3 H), 2.81 (s, 3 H), 2.54 - 2.63 (m, 1 H), 2.02 - 2.11 (m, 1 H), 1.83 1.94 (m, 1 H), 1.62 - 1.73 (m, 1 H), 1.43 - 1.60 (m, 2 H), 1.25 - 1.36 (m, 1 H). Example 36 (+)-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 R*,3S*)-3 25 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide F N -O N xN ON/ rac-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3R*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 35) was separated by supercritical fluid chiral chromatography (Chiralcel OJ-H 30 column, 30 x 250 mm, 25% methanol, 70 mL/min). Isolation of the first eluting isomer afforded the title compound (34.1 mg). MS (ES+) m/z 519 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.45 (t, J=6.2 129 WO 2009/016498 PCT/IB2008/002046 Hz, 1 H), 8.37 (s, 1 H), 7.03 - 7.16 (m, 3 H), 6.83 - 6.89 (m, 1 H), 4.77 (d, J=7.3 Hz, 2 H), 4.46 (d, J=6.2 Hz, 2 H), 3.78 (s, 3 H), 3.57 - 3.65 (m, 1 H), 2.83 (s, 3 H), 2.78 (s, 3 H), 2.51 - 2.60 (m, 1 H), 2.00 - 2.09 (m, 1 H), 1.82 - 1.91 (m, 1 H), 1.59 - 1.70 (m, 1 H), 1.41 - 1.58 (m, 2 H), 1.22 - 1.33 (m, 1 H). [a]D 21 0 = +2.9 0 .(c = 0.7, dichloromethane) 5 Example 37 (-)-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3R*)-3 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide F N 0 H N N N.N N 0 H rac-N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3R*)-3 10 (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 35) was separated by supercritical fluid chiral chromatography (Chiralcel OJ-H column, 30 x 250 mm, 25% methanol, 70 mL/min). Isolation of the second eluting isomer afforded the title compound (36.9 mg). MS (ES+) m/z 519 (M+H). 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.50 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 7.08 - 7.21 (m, 3 H), 6.88 - 6.94 (m, 1 H), 4.82 (d, J=7.3 Hz, 2 H), 4.51 15 (d, J=6.2 Hz, 2 H), 3.82 (s, 3 H), 3.62 - 3.70 (m, 1 H), 2.87 (s, 3 H), 2.83 (s, 3 H), 2.55 - 2.65 (m, 1 H), 2.04 - 2.13 (m, 1 H), 1.86 - 1.96 (m, 1 H), 1.65 - 1.74 (m, 1 H), 1.46 - 1.62 (m, 2 H), 1.27 - 1.37 (m, 1 H). [a]D o = 4.8'(c = 0.7, dichloromethane) Example 38 N-(3-Methoxybenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yI)pyrimidine-4 20 carboxamide HN 0H -O N N N N N' CO N-(3-Methoxybenzyl)-2-m ethyl-6-(2H-tetrazol-5-yl)pyrim idine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-m ethylpyrimidine-4-carboxamide, Example 5) (0.656 g, 2.02 mmol) and (S)-ted 25 butyl 2-(hydroxymethyl)morpholine-4-carboxylate (438 mg, 2.02 mmol) were taken up in tetrahydrofuran (25 mL) and treated with polymer supported triphenylphosphine (1.34 g, 3.02 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (557 mg, 2.42 mmol) was added. After 36 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated to a crude residue as a yellow oil. The residue was purified via normal phase 30 chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1% methanol ran through entire gradient). Fractions containing (2S)-terf-butyl 2-((5-(6-((3-methoxybenzyl)carbamoyl)-2 130 WO 2009/016498 PCT/IB2008/002046 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)morpholine-4-carboxylate were concentrated. The residue was taken up in dichloromethane (5 mL) and stirred with trifluoroacetic acid (1 mL). After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2.5 N aqueous NaOH to pH 7-8. The organic layer was separated and washed with 5 water, dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0.28 g) containing the title compound. LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.9 min, m/z 525 (M+H). Example 39 N-(3-Methoxybenzyl)-6-(2-(((S)-4-acetylmorpholin-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide / -H 0 0 r - HN -oN NaN N 10 N N N - CO A regioisomeric mixture (0.13 g) containing N-(3-methoxybenzyl)-2-methyl-6-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 38) was taken up in dichloromethane (2 mL) and treated with triethylamine (0.047 mL, 0.38 mmol) and a solution of acetyl chloride (0.033 mL, 0.46 mmol) in dichloromethane (1 mL). After stirring for 2 h at 15 room temperature, the mixture was concentrated and purified via reverse phase chromatography (40 60% acetonitrile/water, 45 min). Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (31 mg, 20%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.52 min, m/z 467 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.01 (3 H, d, J=1 7.0 Hz), 2.56 - 2.74 (1 H, m), 2.81 (3 H, s), 3.40 (1 H, d, J=1 1.0 Hz), 3.63 (1 H, d, J=1 1.0 Hz), 3.71 (3 H, s), 3.79 (1 H, d, J=7.9 20 Hz), 3.88 - 4.13 (2 H, m), 4.37 (1 H, d, J=14.3 Hz), 4.49 (2 H, d, J=6.2 Hz), 4.85 - 5.07 (2 H, m), 6.80 (1 H, d, J=7.9 Hz), 6.91 (2 H, br. s.), 7.14 - 7.29 (1 H, m), 8.40 (1 H, s), 9.47 (1 H, s). Example 40 N-(3-Methoxybenzyl)-2-methyl-6-(2-(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide 0 0 - HN :: -O ' NN N N 25 A regioisomeric mixture (0.13 g) containing N-(3-methoxybenzyl)-2-methyl-6-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 38) was taken up in dichloromethane (2 mL) and treated with triethylamine (0.047 mL, 0.38 mmol) and a solution of methane sulfonyl chloride (0.026 mL, 0.32 mmol) in dichloromethane (1 mL). After stirring 30 for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-60% acetonitrile/water, 45 min). Under these conditions, isolation of the first 131 WO 2009/016498 PCT/IB2008/002046 compound to elute afforded the title compound as a white solid (34 mg, 22%). LC/MS (5%-95%
CH
3
CN/H
2 0, 6 min): 3.99 min, m/z 503 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.68 - 2.88 (5 H, m), 2.91 (3 H, s), 3.34 (1 H, br. s.), 3.50 (1 H, t, J=10.8 Hz), 3.67 (1 H, d, J=1 1.7 Hz), 3.71 (3 H, s), 3.89 (1 H, d, J=11.0 Hz), 4.13 (1 H, t, J=9.0 Hz), 4.49 (2 H, d, J=6.4 Hz), 4.89 - 5.00 (1 H, m), 5.03 5 5.13 (1 H, m), 6.80 (1 H, d, J=6.6 Hz), 6,91 (2 H, br. s.), 7.22 (1 H, t, J=8.1 Hz), 8.40 (1 H, s), 9.47 (1 H, s). Example 41 N-(4-FIuoro-3-methoxybenzyl)-2-methyl-6-(2-((S)-morpholin-2-yImethyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide F 0 N N ' O 10 N- (4- FlIuoro-3- methoxyben zyl)-2 -m ethyl -6-(2 H-tetrazol -5-yl)p yri mid ine-4 -ca rboxa mid e (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (1.00 g, 2.91 mmol) and (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (633 mg, 2.91 mmol) were 15 taken up in tetrahydrofuran (50 mL) and treated with polymer supported triphenylphosphine (1.94 g, 4.37 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (895 mg, 3.50 mmol) was added. After 15 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated to a crude oily residue. The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1% methanol ran through entire 20 gradient). Fractions containing (2S)-tert-butyl 2-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)morpholine-4-carboxylate were concentrated. The residue was taken up in dichloromethane (10 mL) and stirred with trifluoroacetic acid (3 mL). After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2.5 N aqueous NaOH to pH 7-8. The organic layer was separated and washed with 25 water (2 mL), dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0.57 g) containing the title compound. LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.33 min, m/z 443 (M+H). Example 42 N-(4-fluoro-3-methoxybenzyl)-6-(2-(((S)-4-acetylmorpholin-2-yl)methyl)-2H-tetrazol-5-yl)-2 30 methylpyrimidine-4-carboxamide 132 WO 2009/016498 PCT/IB2008/002046 F N -P HN r -O N N N N N NN CN NO A regioisomeric mixture (0.065 g) containing N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 41) was taken up in dichloromethane (2 mL) and treated with triethylamine (0.033 mL, 0.24 mmol) and 5 a solution of acetyl chloride (0.016 mL, 0.23 mmol) in dichloromethane (1 mL). After stirring for 2 h at room temperature, the mixture was concentrated and the crude residue was purified via reverse phase chromatography (40-60% acetonitrile/water, 45 min). Under these conditions, isolation of the first peak to elute afforded the title compound as a white solid (35 mg, 49%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.75 min, m/z 485 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.94 - 2.02 (3 H, m), 2.58 - 2.73 10 (1 H, m), 2.85 (3 H, s), 3.04 - 3.20 (1 H, m), 3.60 (1 H, d, J=13.2 Hz), 3.67 - 3.76 (1 H, m), 3.80 (3 H, s), 3.83 - 3.93 (1 H, m), 3.97 - 4.06 (1 H, m), 4.40 (1 H, d, J=13.2 Hz), 4.49 (2 H, d, J=6.4 Hz), 4.93 5.01 (1 H, m), 5.08 (1 H, d, J=9.7 Hz), 6.83 - 6.92 (1 H, m), 7.06 - 7.20 (2 H, m), 8.46 (1 H, s), 9.54 (1 H, t, J=6.0 Hz). Example 43 15 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-2H tetrazol-5-yl)pyrimidine-4-carboxamide F 0 0 - HN O . -O / NN N N X I N N A regioisomeric mixture (0,15 g) containing N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 20 41) was taken up in dichloromethane (3 mL) and treated with triethylamine (0.052 mL, 0.37 mmol) and a solution of methane sulfonyl chloride ( 0.029 mL, 0.34 mmol) in dichloromethane (1 mL). After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-60% acetonitrile/water, 55 min). Under these conditions, isolation of the first eluted compound afforded the title compound as a white solid (68 mg, 39%). LC/MS (5%-95% 25 CH 3
CN/H
2 0, 6 min): 3.94 min. m/z 521 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.73 - 2.88 (5 H, m), 2.91 (3 H, s), 3.32 (1 H, d, J=1 1.3 Hz), 3.44 - 3.55 (1 H, m), 3.65 (1 H, s), 3.80 (3 H, s), 3.89 (1 H, d, J=11.7 Hz), 4.06 - 4.16 (1 H, m), 4.48 (2 H, d, J=6.4 Hz), 4.89 - 4.99 (1 H, m), 5.01 - 5.12 (1 H, m), 6.89 (1 H, br. s.), 7.06 - 7.21 (2 H, m), 8.40 (1 H, s), 9.49 (1 H, t, J=6.4 Hz). Example 44 30 N-(3-Methoxybenzyl)-2-methyl-6-(2-((R)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4 carboxamide 133 WO 2009/016498 PCT/IB2008/002046 - HN H -0 N~ NN N ON NN N-(3-Methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (1.00 g, 3.07 mmol) and (R)-tert-butyl 5 2-(hydroxymethyl)morpholine-4-carboxylate (801 mg, 3.69 mmol) were taken up in tetrahydrofuran (50 mL) and treated with polymer supported triphenylphosphine (2.05 g, 4.61 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (849 mg, 3.69 mmol) was added. After 15 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated to a crude oily residue. The residue was purified via normal phase chromatography (silica, 0-75% ethyl 10 acetate/heptane with a trace 1% methanol ran through entire gradient). Fractions containing (2R)-tert butyl 2-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)morpholine-4-carboxylate were concentrated. The residue was taken up in dichloromethane (10 mL) and stirred with trifluoroacetic acid (3 mL). After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2.5 N aqueous NaOH to pH 15 7-8. The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0.85 g) containing the title compound. LC/MS (5%-95%
CH
3
CN/H
2 0, 6 min): 2.69 min, m/z 425 (M+H). Example 45 N-(3-Methoxybenzyl)-6-(2-(((R)-4-acetylmorpholin-2-yl)methyl)-2H-tetrazol-5-yl)-2 20 methylpyrimidine-4-carboxamide O 0 HN -O N N N N A regioisomeric mixture (0.42 g) containing N-(3-methoxybenzyl)-2-methyl-6-(2-((R) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 44) was taken up in dichloromethane (4 mL) and treated with triethylamine (0.193 mL, 1.4 mmol) and 25 a solution of acetyl chloride (0.077 mL, 0.1.1 mmol) in dichloromethane (1 mL). After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40 60% acetonitrile/water, 60 min). Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (67 mg, 15%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.66 min, m/z 467 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 2.01 (3 H, d, J=1 7.0 Hz), 2.59 - 2.73 (1 H, 30 m), 2.81 (3 H, s), 3.42 (1 H, t, J=11.0 Hz), 3.63 (1 H, d, J=13.0 Hz), 3.71 (3 H, s), 3.80 (1 H, d, J=9.7 Hz), 3.89 - 4.13 (2 H, m), 4.37 (1 H, d, J=13.0 Hz), 4.49 (2 H, d, J=6.4 Hz), 4.86 - 5.09 (2 H, m), 6.80 (1 H, d, J=7.7 Hz), 6.91 (2 H, br. s.), 7.22 (1 H, t, J=8.1 Hz), 8.40 (1 H, s), 9.47 (1 H, t, J=6.4 Hz). 134 WO 2009/016498 PCT/IB2008/002046 Example 46 N-(3-Methoxvbenzyl)-2-methyl-6-(2-(((S)-4-(methylsulfonvl)morpholin-2-yI)methvl)-2H-tetrazol-5 vl)pyrimidine-4-carboxamide 0 0 -- O Nz N -o/ \\ , NN N NO 5 A regioisomeric mixture (0.42 g) containing N-(3-methoxybenzyl)-2-methyl-6-(2-((R) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 44) was taken up in dichloromethane (5 mL) and treated with triethylamine (0.193 mL, 1.40 mmol) and a solution of methane sulfonyl chloride (0.087 mL, 1.1 mmol) in dichloromethane (1 mL). After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase 10 chromatography (40-60% acetonitrile/water, 60 min). Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (43 mg, 9%). LC/MS (5%-95%
CH
3
CN/H
2 0, 6 min): 3.95 min, m/z 503 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.71 - 2.88 (5 H, m), 2.91 (3 H, s), 3.32 (1 H, d, J=13.0 Hz), 3.42 - 3.54 (1 H, m), 3.67 (1 H, d, J=11.7 Hz), 3.71 (3 H, s), 3.89 (1 H, d, J=12.1 Hz), 4.13 (1 H, t, J=9.0 Hz), 4.49 (2 H, d, J=6.4 Hz), 4.85 - 5.01 (1 H, m), 5.01 15 5.12 (1 H, m), 6.80 (1 H, d, J=8.1 Hz), 6.91 (2 H, br. s.), 7.22 (1 H, t, J=8.1 Hz), 8.40 (1 H, s), 9.47 (1 H, t, J=6.3 Hz). Example 47 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide F 0 O -P HN H Cl NN - N N CI( N N X K -N N'- , 20 Step 1: Preparation of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-Vl)pyrimidine-4 carboxamide F 0 N HN Cl \ \ N H N N' Methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (prepared as described in step 1 25 of the synthesis of N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 17) (3.03 g, 13.8 mmol), 3-chloro-4-fluorobenzylamine (2.31 g, 14.4 mmol) and triethylamine (2.78 g, 27.5 135 WO 2009/016498 PCT/IB2008/002046 mmol) were combined in dimethylacetamide (30 mL). The resulting mixture was stirred at 25 0C for 18 h. The solvent was removed and the product was slurried with 3N hydrochloric acid (100 mL). The precipitate was collected by suction filtration, washed with water (2 x 25 mL) and dried under vacuum to afford the title compound as a tan solid (2.08 mg, 44%). LC/MS (10%-90% CH 3
CN/H
2 0, 4 min): 5 2.74 min, m/z 348 (M+H). Step 2: Preparation of (2S)-tert-butyl 2-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin 4-yl)-2H-tetrazol-2-yl )methyl~morpholine-4-carboxylate F 0 O -P HN r Cl N N N N N ' -N N- -,)C N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (750 mg, 10 2.16 mmol) and (S)-terd-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (562 mg, 2.59 mmol) were taken up in tetrahydrofuran (40 mL) and treated with polymer supported triphenylphosphine (1.44 g, 3.24 mmol). After stirring for 30 min at room temperature, di-tert-butyl azodicarboxylate (596 mg, 2.59 mmol) was added. After 36 h at room temperature, the reaction was filtered to remove the resin. The filtrate was concentrated and the residue was purified via normal phase chromatography (silica, 0-75% 15 ethyl acetate/heptane with a trace 1% methanol ran through entire gradient). The resulting regioisomeric mixture was further purified by reverse phase chromatography (40-65%, acetonitrile/water, 60 minutes). Isolation of the first compound to elute afforded the title compound (0.10 g, 8%). Step 3: Preparation of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H 20 tetrazol-5-vl)pyrimidine-4-carboxamide F 0 -P HN H CI fN N N ' O (2S)-tert-Butyl 2-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H tetrazol-2-yl)methyl)morpholine-4-carboxylate, (0.10 g, 0.18 mmol) was taken up in dichloromethane (1 mL) and stirred with trifluoroacetic acid (0.5 mL). After 3 h stirring at room temperature, additional 25 dichloromethane (5 mL) was added and the reaction was neutralized with 2.5 N aqueous NaOH to pH 7-8. The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to afford the title compound as an oil (0.065 g, 7%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.30 min, m/z 447 (M+H). 136 WO 2009/016498 PCT/IB2008/002046 Example 48 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-2H tetrazol-5-yl)pyrimidine-4-carboxamide F 0 - HN 0:::S Cl / NN N NZO N N N- C ) 5 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in Example 47) (0.065 g, 0.15 mmol) was taken up in dichloromethane (2 mL) and treated with triethylamine (0.018 mL, 0.11 mmol) and a solution of methane sulfonyl chloride (13.5 mg, 0.19 mmol) in dichloromethane (0.5 mL). After stirring for 2 h at room temperature, the mixture was concentrated. The resulting residue was triturated with diethyl 10 ether to afford the title compound as a beige solid (38.5 mg, 68%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 4.23 min, 525 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.71 - 2.87 (5 H, m), 2.89 (3 H, s), 3.27 - 3.33 (1 H, m), 3.41 - 3.52 (1 H, m), 3.64 (1 H, d, J=11.5 Hz), 3.86 (1 H, d, J=9.2 Hz), 4.06 - 4.15 (1 H, m), 4.47 (2 H, d, J=6.2 Hz), 4.86 - 4.97 (1 H, m), 5.00 - 5.08 (1 H, m), 7.28 - 7.36 (2 H, m), 7.52 (1 H, d, J=7.9 Hz), 8.37 (1 H, s), 9.56 (1 H, t, J=6.2 Hz) 15 Example 49 N-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-vlmethyl)-2H-tetrazo-5-yl)pyrimidine-4 carboxamide F N H HN 0H N N' ' Step 1: Preparation of ethyl 3-bromo-4-fluorobenzoate Br 20 0 To a solution of 3-bromo-4-fluorobenzoic acid (48 g, 219.18 mmol) in ethanol (250 mL) was added conc. H 2
SO
4 (15 mL) and the mixture was refluxed for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane (2 x 300 mL). The combined organic layers were washed with saturated NaHCO 3 solution followed by brine 25 solution, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (50.5 g, 93 %). 137 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of ethyl 3-ethyl-4-fluorobenzoate F0 0 Ethylmagnesium bromide (2.0 M in ether, 137.61 mL, 275.23 mmol) was added slowly to a solution of anhydrous ZnC1 2 (37.43 g, 275.23 mmol) in dry tetrahydrofuran (200 mL) under argon 5 atmosphere. The resulting white slurry was stirred at 50 *C for 3 h. In a separate flask, a solution of ethyl 3-bromo-4-fluorobenzoate (17 g, 68.80 mmol) in dry tetrahydrofuran (50 mL) was sequentially treated with PdCl 2 (dppf) (2.8 g, 3.44 mmol) and copper(l) iodide (0.78 g, 4.12 mmol) under an argon atmosphere and the mixture was stirred at room temperature for 30 min. The alkyl zinc slurry was added to the ester mixture at room temperature. The resulting brown slurry was stirred in the dark at 10 room temperature for 48 h. The reaction mixture was concentrated under vacuum to give a dark brown residue which was taken up in ethyl acetate (750mL) and washed sequentially with 1N hydrochloric acid (300 mL) solution, sat. NaHCO 3 (200 mL) solution and brine (250 mL) solution. The organic layer was concentrated in vacuo to obtain crude material which was purified by column chromatography over silica gel (100-200 mesh) using 5 % EtOAc in hexane as an eluent to afford the title compound 15 (12.5 g, 93 %). Step 3: Preparation of 3-ethyl-4-fluorobenzoic acid F OH 0 Ethyl 3-ethyl-4-fluorobenzoate (12.5 g, 63.7 mmol) and lithium hydroxide monohydrate were taken up in dioxane (250 mL) and water (1/1) and stirred overnight at room temperature. The reaction 20 mixture was concentrated under reduced pressure and the residue was acidified with 1N hydrochloric acid under ice-water cold conditions. The mixture was extracted with dichloromethane (2 x 150 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated to afford the title compound (10 g, 95 %). Step 4: Preparation of 3-ethyl-4-fluorobenzamide F
NH
2 25 0 3-Ethyl-4-fluorobenzoic acid (10.3 g, 61.3 mmol) was taken up in SOC1 2 (150 mL) and then refluxed for 4 h. The SOC1 2 was removed under reduced pressure and the residue was dissolved in dry acetonitrile (100 mL). Ammonia gas was passed through the solution at -78*C for 10 min. and the reaction mixture was allowed to warm to room temperature very slowly and stirred overnight. The 30 reaction mixture was concentrated to a residue which was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with sat. NaHCO 3 solution followed by brine solution, 138 WO 2009/016498 PCT/IB2008/002046 dried over sodium sulfate, and concentrated. The residue was washed with hexane to afford the title compound (9.0 g, 88 % ). Step 5: Preparation of (3-ethyl-4-fluorophenyl)methanamine
NH
2 5 Borane dimethylsulfide complex (94%, 22 mL, 215.49 mmol) was added slowly to a solution of 3-ethyl-4-fluorobenzamide (9.0 g, 53.87 mmol) in dichloromethane (200 mL) under ice-cold condition. After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h. The reaction mixture was cooled to O *C and washed with NaHCO 3 solution followed by brine. The organic layer was concentrated to a crude material which was purified by column chromatography 10 over silica gel (100-200 mesh) using 15 % dichloromethane in hexane as an eluent to afford (3-ethyl 4-fluorophenyl)methanamine as a solid (4.8 g, 58 %). MS (ES+) m/z 154 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.23 (t, 3 H) 1.76 (br. s., 1 H) 2.67 (q, 2 H), 3.77 (br. s., 1 H), 3.88 (s, 2 H), 7.01-7.15 (m, 3 H) Step 6: Preparation of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 15 carboxamide F 0 HN N N'NH N / _N WNH A solution of methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 17) (1.0 g, 20 4.54 mmol) in dimethylformamide (5 mL) was treated with (3-ethyl-4-fluorophenyl)methanamine (2.09 g, 13.6 mmol) and heated to 65 *C for 3 days. The mixture was cooled to room temperature. Excess 2.5 N NaOH was added to the mixture, The product mixture was washed with ethyl acetate (3 x 10 mL). Concentrated hydrochloric acid was added and the resulting precipitate was filtered, washed with water and dried in vacuo to afford the title compound (367 mg, 24%). 25 Step 7: Preparation of (S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate 0 / -O N 0 0 (S)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.00 g, 23.0 mmol) was taken up in pyridine (10 mL) and then treated with p-toluene sulfonyl chloride (5.70 g, 29.9 mmol). The reaction was allowed to stir at room temperature for 15 h. The mixture was poured into cold water (50 mL) and 139 WO 2009/016498 PCT/IB2008/002046 extracted with ethyl acetate (2 x 50 mL). The organic layers were washed with water (3 x 40 mL) followed by brine (40 mL), dried over sodium sulfate, and concentrated. The residue was purified on normal phase silica (50 g, 0-75% ethyl acetate/heptane) to afford the title compound as a white solid (7.3 g, 85%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.17 min, m/z 394 (M+Na). 5 Step 8: Preparation of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol 5-yl)pyrimidine-4-carboxamide F 0 - HN H / \ NZ: N N N N N' C) N-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (430 mg, 1.26 mmol) and (S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate (515 mg, 1.39 mmol) were 10 taken up in triethylamine (7.0 mL) and dimethylformamide (0.010 mL). The reaction was stirred at 80 *C for 15 h and was then concentrated. This residue was purified on normal phase silica (20 g, 0-75% ethyl acetate/heptane with 1% methanol trace running throughout gradient). Fractions containing (2S) tert-butyl 2-((5-(6-((3-ethyl-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)morpholine-4-carboxylate were concentrated. The residue was taken up in dichloromethane 15 (4 mL) and stirred with trifluoroacetic acid (1 mL) for 2 h at room temperature. Additional dichloromethane (5 mL) was added and the reaction was neutralized with 2.5 N aqueous NaOH to pH 7-8. The organic layer was separated, dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0.41 g) containing the title compound. LC/MS (5%-95%
CH
3
CN/H
2 0, 6 min): 2.46 min, m/z 441 (M+H). 20 Example 50 N-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-(((R)-4-(methylsulfonyl)morpholin-2-vl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide F /0 0 FN OS N N N N N N-N 'C A regioisomeric mixture (0.40 g) containing N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S) 25 morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in Example 49) (0.40 g, 0.91 mmol) was taken up in dichloromethane (2 mL) and treated with triethylamine (0.512 mL, 1.09 mmol) and a solution of methane sulfonyl chloride (114 mg, 1.00 mmol) in dichloromethane (0.5 mL). After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-65% acetonitrile/water, 60 minutes) to afford the title compound as 30 a white solid (36 mg, 8%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 4.41 min, 519 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.06 - 1.16 (2 H, m), 1.21 (2 H, d, J=5.3 Hz), 2.55 (1 H, s), 2.70 - 2.83 (4 H, 140 WO 2009/016498 PCT/IB2008/002046 m), 2.89 (3 H, s), 3.21 - 3.35 (1 H, m), 3.40 - 3.52 (1 H, m), 3.59 - 3.71 (1 H, m), 3.86 (1 H, d, J=1 1.0 Hz), 4.01 - 4.14 (1 H, m), 4.44 (2 H, d), 4.87 - 4.97 (1 H, m), 4.99 - 5.07 (1 H, m), 6.95 - 7.04 (2 H, m), 7.16 (1 H, d, J=5.5 Hz), 7.22 - 7.29 (1 H, m), 8.38 (1 H, s), 9.46 (1 H, t, J=6.5 Hz) Example 51 5 rac-6-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4 carboxamide N -O N N 0 o N NNO A mixture of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 10 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (300 mg, 0.92 mmol), 2-iodomethyl-1,4-dioxane (421 mg, 1.84 mmol), triethylamine (0.51 mL, 3.69 mmol) and dimethylacetamide (0.5 mL) was stirred at 85 *C for 2 days. The mixture was purified by reverse phase preparative HPLC. Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (146 mg, 37%). LC/MS (5%-95% 15 CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.75 min, m/z 426 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.83 (s, 3 H), 3.38 - 3.59 (m, 3 H), 3.65 (d, J=10.6 Hz, 1 H), 3.73 - 3.75 (m, 4 H), 3.91 (dd, J=11.5, 2.38 Hz, 1 H), 4.11 - 4.20 (m, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.93 (d, J=6.2 Hz, 2 H), 6.89 - 6.96 (m, 2 H), 7.24 (t, J=8.05 Hz, 1 H), 8.42 (s, 1 H), 9.49 (t, J=6.4 Hz, 1 H). Example 52 20 rac-6-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide F N -O N N N NN O A mixture of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 25 (trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (300 mg, 0.87 mmol), 2-iodomethyl-1,4-dioxane (399 mg, 1.75 mmol), triethylamine (0.97 mL, 6.99 mmol) and dimethylacetamide (0.5 mL) was stirred at 85 *C for 2 days. The mixture was purified by reverse phase preparative HPLC. Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (147 mg, 38%). LC/MS (5%-95% 30 CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.78 min, m/z 444 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 141 WO 2009/016498 PCT/IB2008/002046 ppm 2.83 (s, 3 H), 3.38 - 3.59 (m, 3 H), 3.65 (d, J=10.6 Hz, 1 H), 3.73 (d, J=1 1.0 Hz, 1 H), 3.83 (s, 3 H), 3.91 (dd, J=11.5, 2.4 Hz, 1 H), 4.09 - 4.21 (m, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.93 (d, J=6.2 Hz, 2 H), 6.87 - 6.95 (m, 1 H), 7.09 - 7.22 (m, 2 H), 8.42 (s, 1 H), 9.51 (t, J=6.2 Hz, 1 H). Example 53 5 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4 carboxamide -O NN N 0 N N ' O Step 1: Preparation of (R)-(1,4-dioxan-2-yl)methanol 0 OH O 0 10 S-Epichlorohydrin (8.00 g, 86.5 mmol) was added drop wise to a stirred solution of chloro-2 ethanol (20.90 g, 259.0 mmol) and boron trifluoride diethyl etherate (0.12 mL, 1.3 mmol) at 45 *C. After 1.5 hours, the reaction mixture was allowed to cool and was diluted with ethyl ether (50 mL). The mixture was washed with water (25 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure with no heating to afford the intermediate, (S)-2-((2 15 chloroethoxy)methyl)oxirane. The oxirane was added drop wise to a stirred solution of sodium hydroxide (8.65 g, 216 mmol) in water (12 mL). The reaction mixture was stirred at room temperature for 2 hours and then was heated at 90 *C for 2 hours. The reaction mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were concentrated to afford the title compound (5.1 g). 20 Step 2: Preparation of (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 0 11 O 0O-S D 0 0 p-Toluene sulfonyl chloride (8.75 g, 45.9 mmol) was added to a solution of (R)-(1,4-dioxan-2 yl)methanol (5.1 g) in pyridine (50 mL). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice cold water and then extracted with dichloromethane (3 x 50 25 mL). The combined organic layers were washed with water (5 x 20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as an amber oil (6.1 g). LC/MS (5%-95%
CH
3
CN/H
2 0, 6 min): 2.50 min, m/z 273 (M+H). 142 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide -O \N N - N N N' 0 A mixture of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide 5 (prepared as described in step 6 of the synthesis of N-(3-Methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (100 mg, 0.307 mmol), (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (167 mg, 0.615 mmol), triethylamine (0.17 mL, 1.23 mmol) and dimethylacetamide (0.3 mL) was stirred at 85 0C for 18 hours. The mixture was purified by reverse phase preparative HPLC. Fractions containing the desired 10 product were combined, isolated and concentrated to afford the title compound as a white solid (39 mg, 30%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.75, m/z 426 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 2.83 (s, 3 H), 3,38 - 3.58 (m, 3 H), 3.64 (d, J=10.8 Hz, 1 H), 3.70 - 3.77 (m, 4 H), 3.92 (dd, J=11.4, 2.4 Hz, 1 H), 4.10 - 4.19 (m, 1 H), 4.51 (d, J=6.5 Hz, 2 H), 4.92 (d, J=1.6 Hz, 2 H), 6.83 (dd, J=9,0, 1.6 Hz, 1 H), 6.90 - 6.95 (m, 2 H), 7.24 (t, J=8.1 Hz, 1 H), 8.42 (s, 1 H), 9.54 15 (t, J=6.4 Hz, 1 H). Example 54 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-y)-N-(4-fluoro-3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide F N -ON N: N 0 N O 20 A mixture of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 (trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (100 mg, 0.291 mmol), (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazot-5-yl)-N-(3-methoxybenzyl) 25 2-methylpyrimidine-4-carboxamide, Example 53) (159 mg, 0.583 mmol), triethylamine (0.16 mL, 1.17 mmol) and dimethylacetamide (0.3 mL) was stirred at 85 *C for 18 hours. The mixture was purified by reverse phase preparative HPLC. Fractions containing the desired product were isolated and concentrated to afford the title compound as a white solid (51 mg, 39%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.78 min, m/z 444 (M+H). 'H NMR (400 MHz, DMSO-d) 6 30 ppm 2.83 (s, 3 H), 3.38 - 3.58 (m, 3 H), 3.65 (d, J=10.6 Hz, 1 H), 3.73 (d, J=11.4 Hz, 1 H), 3.83 (s, 3 H), 3.91 (dd, J=1 1,5, 2.4 Hz, 1 H), 4.11 - 4.19 (m, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.93 (d, J=6.2 Hz, 2 H), 6.88 - 6.94 (m, 1 H), 7.09 - 7.22 (m, 2 H), 8.42 (s, 1 H), 9.51 (t, J=6.4 Hz, 1 H). 143 WO 2009/016498 PCT/IB2008/002046 Example 55 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-2 methylpyrimidine-4-carboxamide F N O C N N 5 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2 ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (150 mg, 0.43 mmol) and (S)-(1,4 dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6 (2-(((R)- 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4 10 carboxamide, Example 53) (129 mg, 0.47 mmol) were taken up in triethylamine (2.00 mL) and dimethylformamide (0.033 mL). The reaction was heated at 90 *C while shaking on a reactor block for 15 h. The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as an oil (29 mg, 15%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 4.25 min, m/z 448 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.81 (3 H, s), 3.35 - 3.57 (3 H, m), 3.62 (1 H, d, 15 J=10.6 Hz), 3.71 (1 H, d, J=1 1.2 Hz), 3.89 (1 H, dd, J=1 1.53, 2.4 Hz), 4.06 - 4.20 (1 H, m), 4.49 (2 H, d, J=6.4 Hz), 4.90 (2 H, d, J=6.4 Hz), 7.35 (2 H, d, J=7.1 Hz), 7.54 (1 H, d, J=7.3 Hz), 8.39 (1 H, s), 9.59 (1 H, t, J=6.2 Hz). Example 56 6-(2-(((R)-1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-2 20 methylpyrimidine-4-carboxamide F 0 O HO O N N O N N K) N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 25 carboxamide, Example 27) (45 mg, 0.20 mmol) and (S)-(1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yi)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, Example 53) (60 mg, 0.22 mmol) were taken up in triethylamine (1.00 mL) and dimethylformamide (0.12 mL). The reaction was heated at 90 *C while shaking on a reactor block for 15 h. The mixture was concentrated 30 and the residue was purified by reverse phase chromatography to afford the title compound as an oil (17 mg, 18%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.43 min, m/z 474 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.81 (3 H, s), 3.35 - 3.57 (3 H, m), 3.62 (1 H, d, J=10.8 Hz), 3.67 - 3.75 (3 H, m), 144 WO 2009/016498 PCT/IB2008/002046 3.89 (1 H, dd, J=11.6, 2.5 Hz), 4.02 (2 H, t, J=5.0 Hz), 4.06 - 4.18 (1 H, m), 4.47 (2 H, d, J=6.2 Hz), 4.81 (1 H, t, J=5.4 Hz), 4.90 (2 H, d, J=6.6 Hz), 6.81 - 6.94 (1 H, m), 7.08 - 7.20 (2 H, m), 8.40 (1 H, s), 9.48 (1 H, t, J=6.3 Hz). Example 57 5 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4 carboxamide P-\N 0 -0 N -O N. : - O N NN Step 1: Preparation of (S)-(1,4-dioxan-2-yl)methanol HO 0 0 10 R-Epichlorohydrin (17.00 g, 180 mmol) was added drop wise to a stirred solution of chloro-2 ethanol (44.4 g, 551 mmol) and boron trifluoride diethyl etherate (1.05 g, 9.19 mmol) at 45 *C. After 18 hours, the reaction was quenched by adding diethyl ether (100 mL). The organic layer was washed with water (100 mL), dried over magnesium sulfate, filtered and evaporated. Purification was accomplished by vacuum distillation (10 torr) affording the desired intermediate as an oil (128-131 *C, 15 18 g, 57%). The intermediate was added drop-wise to a stirred solution of sodium hydroxide (10.4 g, 260 mmol) in water (15 mL). The reaction was stirred at room temperature for 1 h, diluted with water (15 mL) and heated at 90 0C for 2 h. The reaction mixture was extracted with dichloromethane (3 x 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a clear oil (7.4 g, 35%). 20 Step 2: Preparation of (R)-(1,4-dioxan-2-vl)methyl 4-methylbenzenesulfonate 0 /\ -0 0D 0 0 (S)-(1,4-Dioxan-2-yl)methanol (2.52 g, 21.3 mmol) was taken up in pyridine (30 mL) and treated with p-toluene sulfonyl chloride (4.11 g, 21.5 mmol) and stirred at 25 *C for 18 hours. The reaction mixture was dripped into ice water, extracted with dichloromethane (3 x 50 mL) and washed 25 with water (5 x 20 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (2.48 g, 43%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4 min): 2.60 min, m/z 273 (M+H). 145 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide HN 0 - HN N N N A mixture of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrim idine-4-carboxamide 5 (prepared as described in step 6 of the synthesis of N-(3-Methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (100 mg, 0.307 mmol), (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (167 mg, 0.615 mmol), triethylamine (0.17 mL, 1.23 mmol) and dimethylacetamide (0.3 mL) was stirred at 85 *C for 18 h. The mixture was purified by reverse phase preparative HPLC. Fractions containing the desired product 10 were isolated and concentrated to afford the title compound as a white solid (46 mg, 35%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.75 min, m/z 426 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 2.84 (s, 3 H), 3.38 - 3.59 (m, 3 H), 3.65 (d, J=10.8 Hz, 1 H), 3.70 - 3.76 (m, 4 H), 3.92 (dd, J=1 1.5, 2.5 Hz, 1 H), 4.11 - 4.20 (m, 1 H), 4.51 (d, J=6.3 Hz, 2 H), 4.93 (d, J=1.8 Hz, 2 H), 6.83 (dd, J=8.1, 1.7 Hz, 1 H), 6.90 - 6.96 (m, 2 H), 7.25 (t, J=8.1 Hz, 1 H), 8.43 (s, 1 H), 9,54 (t, J=6.5 15 Hz, 1 H). Example 58 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide F N -O N N NO 20 A mixture of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 (trans-4-aminocyclohexyl)methyl)-2H-tetrazo-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (100 mg, 0.291 mmol), (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl) 25 2-methylpyrimidine-4-carboxamide, Example 57) (159 mg, 0.583 mmol), triethylamine (0.16 mL, 1.17 mmol) and dimethylacetamide (0.3 mL) was stirred at 85 0C for 18 hours. The mixture was purified by reverse phase HPLC, Fractions containing the desired product were concentrated to afford the title compound as a white solid (41 mg, 32%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2,78 min, m/z 444 m/z (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.83 (s, 3 H) 3.38 - 3.59 (m, 3 H) 30 3.65 (d, J=10.6 Hz, 1 H) 3.73 (d, J=1 1.4 Hz, 1 H) 3.83 (s, 3 H) 3.91 (dd, J=1 1.5, 2.38 Hz, 1 H) 4.15 (q, J=6.2 Hz, 1 H) 4.51 (d, J=6.2 Hz, 2 H) 4.93 (d, J=5.5 Hz, 2 H) 6.88 - 6.95 (m, 1 H) 7.09 - 7.22 (m, 2 H) 8.42 (s, 1 H) 9.50 (t, J=6.22 Hz, 1 H). 146 WO 2009/016498 PCT/IB2008/002046 Example 59 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-chloro-4-fluorobenzyl)-2 methylpyrimidine-4-carboxamide F N CI N N N 5 N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2 ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (100 mg, 0.288 mmol), (R)-(1,4 dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6 (2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4 10 carboxamide, Example 57) (78.3 mg, 0.288 mmol), and triethylamine (400 pL) were combined in dimethylacetamide (100 pL). The resulting mixture was stirred at 90 *C for 18 h. The mixture was concentrated. The residue was purified by reverse phase high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (8 mg, 6%). MS (ES+) m/z 448 (M+H). 1 H 15 NMR (400 MHz, DMSO-d) 6 ppm 9.48 (m, 1 H), 8.40 (s, 1 H), 7.54(m, 1 H), 7.24 (m, 2 H), 4.91 (m, 2 H), 4.51 (m, 2 H), 4.18 (m, 1 H), 3.81 (m, 1 H), 3.42-3.72 (m, 5 H), 2.81 (s, 3 H). Example 60 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-2 methylpyrimidine-4-carboxamide F N 0 - HN 0Nz /\ NN 0 HO- ON N 20 O N N NO 20 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 27) (56.7 mg, 0.152 mmol), (R)-(1,4-dioxan-2-yl)methyl 4 25 methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((S)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, Example 57) (400 pL) and triethylamine (30.7 mg, 0.304 mmol) were combined in dimethylacetamide (100 pL). After heating the reaction at 90 0C for 18 h, the mixture was concentrated. The residue was purified by reverse phase high-pressure liquid chromatography. The pure fractions were combined, extracted with 30 ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as an oil (12.1 mg, 17%). MS (ES+) m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 147 WO 2009/016498 PCT/IB2008/002046 9.48 (m, 1 H), 8.41 (s, 1 H), 7.20 (m, 3 H), 6.84 (m, 1 H), 4.88 - 4.94 (m, 4 H), 4.81 (t, 1 H), 4.42 - 4.48 (m, 2 H), 4.10 - 4.16 (m, 1 H), 3.99 - 4.06 (m, 2 H), 3.84 - 3.93 (m, 2 H), 3.67 - 3.73 (m, 1 H), 3.57 3.65 (m, 1 H), 3.35 - 3.55 (m, 1 H), 2.81 (s, 3 H). Example 61 5 rac-N-(3-Methoxybenzyl)-6-(2-(((2S,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yI)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide NH - OH 0 N Step 1: Preparation of trans-2,5-bis(iodomethyl)-1 ,4-dioxane 10 Yellow mercury oxide (700 g, 3.23 mol) was dissolved in concentrated nitric acid (70%, 443 mL, 6.53 mol) and water (295 mL). To the solution was added water (1180 mL) and it was cooled to O *C. Allyl alcohol (445 mL, 6.53 mol) was added in portions while the temperature was at 0-10 *C. After addition, the mixture was stirred for 6 h. The precipitate was collected by filtration and washed with water, The solid was dissolved in 10% NaOH (1.94 L, 4.85 mol) and the solution was basic. 15 Concentrated potassium iodide (805 g, 4.85 mol) in water (560 mL) was added until precipitation of the mercury intermediate was complete. The precipitate was collected and washed with water. The wet solid was mixed with iodine (1041 g, 1.11 mol) and potassium iodide (1492 g, 8.99 mol) in water (3.7 L). The mixture was heated to reflux for 24 h. A few mL of benzene was added to wash back iodine that sublimed on the condenser. After 24 hr, the mixture was cooled to room temperature. The 20 precipitate was filtered, washed with dilute NaHSO 3 and water to provide the title compound (598 g, 25%). Step 2: Preparation of trans-2,5-bis-(acetoxymethyl)-1,4-dioxane 0 OO 0 A mixture of trans-2,5-bis(iodomethyl)-1,4-dioxane (523 g, 1.42 mol) and potassium acetate 25 (956 g, 9.74 mol) in acetic acid (3.35 L) was heated to reflux. The solution was seeded with 7 g of potassium iodide. The resulting mixture was heated to gently reflux for nine days. The dark mixture was cooled down and filtered to remove the solid. The filtrate was concentrated to remove half of the solvent and then diluted with ethyl acetate (5 L), and filtered. The filtrate was concentrated, and the residue was triturated with water (5 L) and cooled in an ice bath to provide the title compound as 30 brown solid (140.5 g). 148 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of trans-2,5-bis-(hydroxymethyl)-1 ,4-dioxane 0 OH HO". O A mixture of trans-2,5-bis-(acetoxymethyl)-1,4-dioxane (213 g) in methanol (1065 mL) and 4N hydrochloric acid in dioxane (229 mL) was heated to reflux for 1 h. About 30 g of decolorizing charcoal 5 was added after cooling down. The mixture was filtered through a pad of CeliteTM. The filtrate was concentrated, and the oily residue was dissolved in isopropyl alcohol/benzene (1/5, 600 mL). Crystals were obtained by filtration and washed with isopropyl alcohol/benzene (1/5) to provide the title compound as a solid (126.9).. Step 4: Preparation of rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-vl)methyl 4 10 methylbenzenesulfonate 0 S-0 0 O O O 0 OH trans-2,5-bis-(Hydroxymethyl)-1,4-dioxane (342.9 g, 2.31 mol) and p-toluene sulfonylchloride (441.0 g, 2.31 mol), triethylamine (471.5 g, 4.66 mol) and dichloromethane (3 L) were combined in a 5 L round-bottomed flask equipped with a mechanical stirrer under nitrogen. The mixture was 15 maintained at 35 *C for 30 min with water bath cooling and than allowed to stir at room temperature overnight. The mixture was diluted with 3 N hydrochloric acid (1 L), and the resulting solids were filtered. The organic phase of the filtrate was separated, washed with 3 N hydrochloric acid (1 L) followed by saturated ammonium chloride solution (500 mL), dried over magnesium sulfate, and concentrated to afford the title compound (338.3 g). 20 Step 5: Preparation of rac-N-(3-Methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2 yI)methyl)-2H-tetrazol-5-vl)-2-methylpVrimidine-4-carboxamide 00 / -N _9 NH - O( ,,0H O N N 0 N rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyI 4-methylbenzenesulfonate (4.3 g, 14.0 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 25 carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (3.2 g, 9.8 mmol) and triethylamine (2.0 g, 19.7 mmol) in anhydrous dimethylacetamide (4 mL). The reaction was stirred at 85 *C in a capped vial overnight. The mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a 30 carbonate resin column and concentrated. The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (1.38 g). MS (ES+) m/z 456 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.44 - 9.52 (1 H, m), 8.42 (1 H, s), 7.24 (1 H, t, J=8.1 149 WO 2009/016498 PCT/IB2008/002046 Hz), 6.89 - 6.95 (2 H, m), 6.83 (1 H, d, J=8.1 Hz), 4.93 (1 H, d, J=3.3 Hz), 4.88 (1 H, d, J=7.7 Hz), 4.51 (3 H, d, J=5.9 Hz), 4.08 (1 H, d, J=3.3 Hz), 3.99 (1 H, d, J=1 1.3 Hz), 3.78 (1 H, d, J=1 1.3 Hz), 3.74 (3 H, s), 3.36 - 3.48 (4 H, m), 3.31 (1 H, d, J=2.2 Hz), 2.83 (3 H, s) Example 62 5 N-(3-Methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide N N O O 0 NN Step 1: Preparation of ((2R,5R)-5-(hydroxymethyl)-1 ,4-dioxan-2-vl)methyl 4-methylbenzenesulfonate 0 OH 0 S-O 0 0 10 rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methy 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) was chirally separated by supercritical fluid chromatography (AD-H; 30% methanol/dichloromethane, 10/1; 200 mL/min). Isolation of the first eluting isomer afforded the title compound as a white solid. 15 Step 2: Preparation of N-(3-methoxybenzvl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide NH O OH O N 0 N 1 ((2R,5R)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (5.2 g, 17.2 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 20 carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (4.0 g, 12.3 mmol) and triethylamine (3.1 g, 30.0 mmol) in anhydrous dimethylacetamide (4 mL). The reaction was stirred at 85 *C in a capped vial overnight. The mixture was purified by reverse phase preparative HPLC (water/acetonitrile), and fractions containing product were concentrated. The residue was 25 dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70 mL/min). Fractions containing the desired product were concentrated and the resulting solid was 150 WO 2009/016498 PCT/IB2008/002046 recrystallized from isopropanol to afford the title compound as a white solid (986 mg). MS (ES+) m/z 456 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 9.52 (1 H, t, J=6.4 Hz), 8.39 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.86-6.92 (2 H, m), 6.77-6.82 (1 H, m), 4.80-4.95 (2 H, m), 4.69 (1 H, t, J=5.5 Hz), 4.47 (2 H, d, J=6.2 Hz), 3.93-4.09 (2 H, m), 3.71-3.77 (1 H, m), 3.70 (3 H, s), 3.2-3.45 (5 H, m), 2.79 (3 H, s). 5 Example 63 N-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide N ON '0 O 0 O N N / OH NH N Step 1: Preparation of ((2S.5S)-5-(hydroxymet yI)-1 ,4-dioxan-2-yI)methyI 4-methylbenzenesulfonate 0 OH - ,s'-a 0 11 10 0 rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) was chirally separated by supercritical fluid chromatography (AD-H; 30% methanol/dichloromethane, 10/1; 200 15 mL/min). Isolation of the second eluting isomer afforded the title compound as a white solid. Step 2: Preparation of N-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)- 1 ,4-dioxan-2-yl)methylV) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide O/ NN O NH
/
0 N ((2S,5S)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (5.2 g, 17.2 20 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (4.0 g, 12.3 mmol) and triethylamine (3.1 g, 30.0 mmol) in anhydrous dimethylacetamide (4 mL). The reaction was stirred at 85 *C in a capped vial overnight. The mixture was purified by reverse phase preparative 25 HPLC (water/acetonitrile), and fractions containing product were concentrated. The residue was dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70 151 WO 2009/016498 PCT/IB2008/002046 mL/min). Fractions containing the desired product were concentrated and the resulting solid was recrystallized from isopropanol to afford the title compound as a white solid (576 mg). MS (ES+) m/z 456 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.52 (1 H, t, J=6.4 Hz), 8.39 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.86-6.92 (2 H, m), 6.77-6.82 (1 H, m), 4.80-4.95 (2 H, m), 4.69 (1 H, t, J=5.5 Hz), 4.47 (2 5 H, d, J=6.2 Hz), 3.93-4.09 (2 H, m), 3.71-3.77 (1 H, m), 3.70 (3 H, s), 3.2-3.45 (5 H, m), 2.79 (3 H, s). Example 64 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F / 0 \ C NH O OH
-
/ N 0 N 10 rac-((2R*,5R*)-5-(Hydroxymethyl)- 1 ,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (2.64 g, 8.7 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-Fluoro-3 15 methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 9) (2.0 g, 5.8 mmol) and triethylamine (880 mg, 8.7 mmol) in anhydrous dimethylacetamide (2 mL). The reaction was stirred overnight at 85 0C in a capped vial. The mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a carbonate resin column and concentrated. The resulting 20 product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (1.02 g). MS (ES+) m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.50 (1 H, t, J=6.2 Hz), 8.42 (1 H, s), 7.15 (2 H, td, J=12.1, 8.4 Hz), 6.92 (1 H, d, J=4.4 Hz), 4.93 (1 H, d, J=3.7 Hz), 4.88 (1 H, d, J=7.7 Hz), 4.65 (1 H, t, J=5.5 Hz), 4.51 (3 H, d, J=6.2 Hz), 4.08 (1 H, d, J=2.9 Hz), 3.99 (1 H, dd, J=1 1.5, 2.0 Hz), 3.83 (3 H, s), 3.78 (1 H, d, J=1 1.7 Hz), 3.36 - 3.48 (4 H, m), 3.31 (1 H, s), 25 2.83 (3 H, s). Example 65 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 152 WO 2009/016498 PCT/IB2008/002046 F O N IN'N ', -- N NH O OH N /N 0 N N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazo-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (10.0 g, 5 29.1 mmol) was dissolved in triethylamine (7.04 g, 69.7 mmol) and N,N-dimethylacetamide (31 mL). ((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 62) (12.4 g, 41.0 mmol) was added and the reaction heated to 85 0C for 16 hours. After cooling to room temperature, the mixture 10 was diluted with water (300 mL) and extracted with dichloromethane (3 x 200 mL). The combined organics were washed with 1N NaOH (2 x 100 mL), 1M hydrochloric acid (2 x 100 mL), water (100 mL), and brine (250 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give a yellow oil. Purification by silica gel chromatography using heptane, ethyl acetate and methanol provided a mixture of regioisomers as an opaque oil. The mixture was separated by supercritical fluid 15 chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70 mL/min) and the desired isomer was recrystallized from ethyl acetate (80 mL) and ethanol (1 mL) to provide the title compound as a white crystalline solid (3.5 g, 25%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min): 3.39 min, m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.53 (t, J=6.3 Hz, 1 H), 8.39 (s, 1 H), 7.06 - 7.19 (m, 2 H), 6.83 - 6.91 (m, 1 H), 4.78 - 4.98 (m, 2 H), 4.68 (t, J=5.7 Hz, 1 H), 4.47 (d, J=6.4 Hz, 2 H), 3.99 - 4.10 (m, 1 H), 3.96 20 (dd, J=11.4, 2.4 Hz, 1 H), 3.79 (s, 3 H), 3.74 (dd, J=11.4, 2.2 Hz, 1 H), 3.19 - 3.47 (m, 5 H), 2.80 (s, 3 H). Example 66 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F 0 NN 0 N O '-,OH O N 25 ((2S,5S)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 63) (5.2 g, 17.2 mmol) was added to a solution of N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5 30 yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3 153 WO 2009/016498 PCT/IB2008/002046 methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 9) (4.22 g, 12.3 mmol) and triethylamine (3.1 g, 30.0 mmol) in anhydrous dimethylacetamide (4 mL). The reaction was stirred at 85 0C in a capped vial overnight. The mixture was purified by reverse phase preparative HPLC (water/acetonitrile), and fractions containing product 5 were concentrated. The residue was dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 45% acetonitrile, 70 mL/min). Fractions containing the desired product were concentrated and the resulting solid was recrystallized from ethyl acetate (80 mL) to 10 afford the title compound as a white solid (1.5 g). MS (ES+) m/z 474 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.50 (1 H, t, J=6.2 Hz), 8.42 (1 H, s), 7.08-7.17 (2 H, m), 6.85-6.9 (1 H, m), 4.80-4.95 (2 H, m), 4.69 (1 H, t, J=5.5 Hz), 4.47 (2 H, d, J=6.2 Hz), 3.93-4.09 (2 H, m), 3.79 (3 H, s), 3.71-3.77 (1 H, m), 3.2-3.45 (5 H, m), 2.79 (3 H, s). Example 67 15 rac-N-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N N'N O N NH O OH N O N Step 1: Preparation of methyl rac-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-vl)-2-methylpyrimidine-4-carboxVlate 0 0 O \ N OH N N' O 20 In a 30 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 17) (1.57 25 g, 7.13 mmol) was dissolved in N,N-dimethylformamide (15ml). N,N-Diisopropylethylamine (1.86 g, 14.40 mmol) was added and the mixture was stirred at room temperature for 30 min. rac-((2R*,5R*)-5 (Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (4.41 g, 14.59 mmol) was added 30 and the reaction mixture was heated to 80 *C with stirring for 14 hours. The reaction mixture was 154 WO 2009/016498 PCT/IB2008/002046 concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak, 20%-35% acetonitrile, 20 min hold, 40 min gradient, 8 min hold). Fractions corresponding to the first eluting peak (27,34 min) were concentrated under vacuum to afford the title compound as a solid (1.4 g) LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 1.856 min, m/z 5 351(M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.16 - 1.27 (m, 2 H), 2.25 (s, 1 H), 2.79 (s, 3 H), 3.11 (dd, J=7.4, 4.2 Hz, 1 H), 3.18 - 3.29 (m, 2 H), 3.29 - 3.46 (m, 2 H), 3.59 (d, J=3.8 Hz, 1 H), 3.74 (dd, J=1 1.6, 2.4 Hz, 1 H), 4.80 - 4.88 (m, 1 H), 4.89 - 4.97 (m, 1 H), 7.08 (d, J=7.8 Hz, 1 H), 7.44 (d, J=8.1 Hz, 1 H), 8.36 (s, 1 H). Step 2: Preparation of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan 10 2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrim idine-4-carboxamide F NH OH //N O N A mixture of rac-methyl 6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (100 mg, 0.285 mmol), 4-fluoro-3-methylbenzylamine (119 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 *C for 18 hours, The title 15 compound was isolated as a solid by reverse phase preparative HPLC (73 mg, 56%). MS (ES+) m/z 458 m/z (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.22 (s, 3 H), 2.83 (s, 3 H), 3.34 - 3.55 (m, 5 H), 3.78 (dd, J=11.5, 2.0 Hz, 1 H), 3.99 (dd, J=11.5, 2.0 Hz, 1 H), 4.04 - 4.16 (m, 1 H), 4.48 (d, J=6.2 Hz, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.80 - 5.00 (m, 2 H), 7.07 (t, J=9.2 Hz, 1 H), 7.16 - 7.24 (m, 1 H), 7.26 (d, J=7.3 Hz, 1 H), 8.42 (s, 1 H), 9.50 (t, J=6.2 Hz, 1 H). 20 Example 68 N-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide F \N 'N ''0 NH N O OH O N 155 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide 0 N-N ,NH H N , N F NT A solution of methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (prepared as 5 described in step 1 of the synthesis of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 17) (1.0 g, 4.54 mmol) in dimethylformamide (5 mL) was treated with 4-fluoro-3-methylbenzylamine (1.9 g, 13.6 mmol) and heated to 65 *C for 3 days. The mixture was cooled to room temperature. Excess 2.5 N NaOH was added to the mixture. The product mixture was washed with ethyl acetate (3 x 10 mL). 10 Concentrated hydrochloric acid was added and the resulting precipitate was filtered, washed with water and dried in vacuo to afford the title compound (1.21 g, 75%). Step 2: Preparation of N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yI)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F N N N ', O O . , N NH O OH N 0 N 15 A mixture of N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (96 mg, 0.293 mmol), ((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-6 (2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 62) (106 mg, 0.352 mmol), and triethylamine (0.16 mL, 1.17 mmol) was heated 20 in dimethylformamide at 85 *C overnight. The mixture was chromatographed by reverse phase preparative HPLC. Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (39 mg, 28%). MS (ES+) m/z 458 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.83 (t, J=5.9 Hz, 1 H), 2.28 (d, J=2.0 Hz, 3 H), 2.89 (s, 3 H), 3.47 3.62 (m, 3 H), 3.62 - 3.71 (m, 2 H), 3.82 (dd, J=11.6, 2.3 Hz, 1 H), 3.99 (dd, J=11.6, 2.4 Hz, 1 H), 4.17 25 - 4.26 (m, 1 H), 4.64 (d, J=6.1 Hz, 2 H), 4.68 - 4.88 (m, 2 H), 6.96 - 7.03 (m, 1 H), 7.14 - 7.23 (m, 2 H), 8.27 - 8.34 (m, 1 H), 8.80 (s, 1 H). Example 69 N-(4-Fluoro-3-methylbenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide 156 WO 2009/016498 PCT/IB2008/002046 F - N NH O '"",OH N A mixture of N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 1 in the synthesis of N-(4-fluoro-3-methylbenzyl)-6-(2 (((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 5 carboxamide, Example 68) (96 mg, 0.293 mmol), ((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-Methoxybenzyl) 6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 63) (106 mg, 0.352 mmol), and triethylamine (0.16 mL, 1.17 mmol) was heated in dimethylformamide at 85 0C overnight. The mixture was chromatographed by reverse phase 10 preparative HPLC. Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (21mg, 16%). MS (ES+) m/z 458 (M+H). 1 H NMR (400 MHz, CDCl 3 ) 6 ppm 2.26 (d, J=1.4 Hz, 3 H), 2.87 (s, 3 H), 3.43 - 3.70 (m, 6 H), 3.79 (dd, J=11,6, 2.1 Hz, 1 H), 3.96 (dd, J=11.5, 2.5 Hz, 1 H), 4.14 - 4.25 (m, 1 H), 4.61 (d, J=6.3 Hz, 2 H), 4.66 - 4.86 (m, 2 H), 6.97 (t, J=8.9 Hz, 1 H), 7.10 - 7.21 (m, 2 H), 8.29 (t, 15 J=5.8 Hz, 1 H), 8.77 (s, 1 H). Example 70 rac-N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F F CN N' 0 N O OH 0 N 20 A mixture of rac-methyl 6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 67) (100 mg, 0.285 mmol), 4-fluoro-3 trifluoromethylbenzylamine (165 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 0C 25 for 18 hours. The title compound was isolated as a solid by reverse phase preparative HPLC (52 mg, 36%). MS (ES+) m/z 512 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.84 (s, 3 H), 3.31 - 3.52 (m, 5 H), 3.78 (dd, J=11.4, 1.8 Hz, 1 H), 3.99 (dd, J=11.4, 2.2 Hz, 1 H), 4.03 - 4.14 (m, 1 H), 4.59 (d, J=6.2 Hz, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.81 - 5.00 (m, 2 H), 7.41 - 7.53 (m, 1 H), 7.69 - 7.83 (m, 2 H), 8.41 (s, 1 H), 9.66 (t, J=6.04 Hz, 1 H). 157 WO 2009/016498 PCT/IB2008/002046 Example 71 rac-N-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F NH OH O N 5 A mixture of methyl rac-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 67) (100 mg, 0.285 mmol), (3-ethyl-4 fluorophenyl)methanamine (prepared as described in steps 1 - 5 of the synthesis of N-(3-ethyl-4 10 fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 49) (131 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 *C for 18 hours. The title compound was isolated as a solid by reverse phase preparative HPLC (57 mg, 42%). MS (ES+) m/z 472 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.12 (t, J=7.7 Hz, 3 H), 2.57 (q, J=7.3 Hz, 2 H), 2.79 (s, 3 H), 3.26 - 3.47 (m, 5 H), 3.74 (dd, J= 11.0, 2.2 Hz, 1 H), 3.95 (dd, J= 11.0, 2.2 Hz, 1 H), 15 4.00 - 4.10 (m, 1 H), 4.46 (d, J=6.6 Hz, 2 H), 4.62 (t, J=5.9 Hz, 1 H), 4.77 - 4.96 (m, 2 H), 6.97 - 7.09 (m, 1 H), 7.13 - 7.21 (m, 1 H), 7.25 (d, J=9.5 Hz, 1 H), 8.38 (s, 1 H), 9.46 (t, J=6.2 Hz, 1 H). Example 72 N-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide F N N'N ''0 N O OH O N 20 A mixture of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in steps 1 - 6 of the synthesis of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 49) (100 mg, 0.293 mmol), ((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described 25 in step 1 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxam ide, Example 62) (106 mg, 0.352 mmol), and triethylamine (0.16 mL, 1.17 mmol) was heated in dimethylformamide at 85 0C overnight. The mixture was chromatographed by reverse phase preparative HPLC. Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (28 30 mg, 20%). MS (ES+) m/z 472 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.23 (t, J=7.5 Hz, 3 H), 1.80 158 WO 2009/016498 PCT/IB2008/002046 (br. s., 1 H), 2.67 (q, J=7.6 Hz, 2 H), 2.89 (s, 3 H), 3.41 - 3.73 (m, 5 H), 3.82 (dd, J=1 1.6, 2.3 Hz, 1 H), 3.99 (dd, J=1 1.5, 2.5 Hz, 1 H), 4.15 - 4.26 (m, 1 H), 4.65 (d, J=6.3 Hz, 2 H), 4.68 - 4.89 (m, 2 H), 7.00 (dd, J=9.7, 8.3 Hz, 1 H), 7.13 - 7.24 (m, 2 H), 8.32 (t, J=6.0 Hz, 1 H), 8.79 (s, 1 H). Example 73 5 N-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide F N 'N O N NH O--OH NH N 0 N A mixture of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in steps 1 - 6 of the synthesis of N-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S) 10 morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 49) (100 mg, 0.293 mmol), ((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 63) (106 mg, 0.352 mmol), and triethylamine (0.16 mL, 1.17 mmol) was heated in dimethylformamide at 85 *C overnight. The 15 mixture was chromatographed by reverse phase preparative HPLC. Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (39 mg, 28%). MS (ES+) m/z 472 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 1.23 (t, J=7.5 Hz, 3 H), 1.72 (br. s., 1 H), 2.67 (q, J=7.5 Hz, 2 H), 2.89 (s, 3 H), 3.46 - 3.70 (m, 5 H), 3.82 (dd, J=1 1.6, 2.3 Hz, 1 H), 3.98 (dd, J=11.5, 2.5 Hz, 1 H), 4.16 - 4.27 (m, 1 H), 4.65 (d, J=6.1 Hz, 2 H), 4.68 - 4.88 (m, 2 H), 7.00 20 (dd, J=9.6, 8.4 Hz, 1 H), 7.14 - 7.24 (m, 2 H), 8.32 (t, J=6.0 Hz, 1 H), 8.79 (s, 1 H). Example 74 rac-N-(4-Fluoro-3-isopropylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N N -N ',0 N O OH O N 0 N 1 159 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of ethyl 4-fluoro-3-isopropylbenzoate F 0 Isopropylmagnesium chloride (2.0 M in ether, 137.61 mL, 275.23 mmol) was added slowly to a solution of anhydrous ZnC1 2 (37.43 g, 275.23 mmol) in dry tetrahydrofuran (200 mL) under an argon 5 atmosphere. The resulting white slurry was stirred at 50 *C for 3 h. In a separate flask, a solution of ethyl 3-bromo-4-fluorobenzoate (prepared as described in step 1 of the synthesis of N-(3-ethyl-4 fluorobenzyl)-2-methyl-6-(2-( (S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 49) (17 g, 68.80 mmol) in dry tetrahydrofuran (150 mL) was sequentially treated with PdCl 2 (dppf) (2.8 g, 3.44 mmol) and copper(l) iodide (0.78 g, 4.12 mmol) under an argon atmosphere. 10 The alkyl zinc slurry was added to the ester mixture at room temperature. The resulting brown slurry was stirred in the dark at room temperature for 48 h. The reaction mixture was concentrated under vacuum to give a dark brown residue, which was taken up in ethyl acetate (750 mL) and washed sequentially with 1N hydrochloric acid (300 mL) solution, sat. NaHCO 3 solution, and brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The crude product was 15 purified by column chromatography over silica gel (100-200 mesh) using 5 % ethyl acetate in hexane as an eluent to afford the title compound (12.5 g, 89%). Step 2: Preparation of 4-fluoro-3-isopropylbenzoic acid F OH 0 Ethyl 4-fluoro-3-isopropylbenzoate (12,5 g, 59.46 mmol) and lithium hydroxide monohydrate 20 (7.49 g, 178.40 mmol) were taken up in a mixture of dioxane/water (1/1, 250 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid under ice-water cold condition. The mixture was extracted with dichloromethane (2 x 150 mL). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound 25 (10 g, 92 %). Step 3: Preparation of 4-fluoro-3-isopropylbenzamide F
NH
2 0 4-Fluoro-3-isopropylbenzoic acid (10.3g, 54.94 mmol) was taken up in SOC1 2 (150 mL) and then refluxed for 4 h. The SOC1 2 was removed under reduced pressure and the resulting residue was 30 dissolved in dry acetonitrile (125 mL). Ammonia gas was passed through the solution at -78 *C for 10 min. The reaction mixture was allowed to warm to room temperature very slowly and stirred for overnight. The reaction mixture was concentrated to a residue which was extracted with 160 WO 2009/016498 PCT/IB2008/002046 dichloromethane (2 x 100 mL). The combined dichloromethane layers were washed with sat. NaHCO 3 solution followed by brine, dried over sodium sulfate, and concentrated. The resulting solid was washed with hexane (2 x 25 mL) to afford the title compound (9 g, 90%). Step 4: Preparation of (4-fluoro-3-isopropylphenyl)methanamine F 5
NH
2 5 Borane dimethylsulfide complex (94 %, 20.33 mL, 198.67 mmol) was added slowly to a solution of 4-fluoro-3-isopropylbenzamide (9 g, 49.66 mmol) in dichloromethane (200 mL) at ice cold condition. After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h. The reaction mixture was cooled to 0 *C, washed with NaHCO 3 solution 10 followed by brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 15 % CH 2 0 2 in hexane as an eluent to afford the title compound (4.8 g, 54%). MS (ES+) m/z 168 (M+H). Step 5: Preparation of rac-N-(4-fluoro-3-isopropylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4 15 dioxan-2-yl)methVl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N N '-, 0 NH -O OH \ /N 0 N A mixture of rac-methyl 6-(2-(((2S*, 5R*)-5-(hydroxymethyl)- 1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 20 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 67) (100 mg, 0.285 mmol), (4-fluoro-3 isopropylphenyl)methanamine (143 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 *C for 18 hours. The title compound was isolated as a solid by reverse phase preparative HPLC (49 mg, 35%). MS (ES+) m/z 486 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.21 (d, J=7.0 Hz, 6 H), 2.83 (s, 3 H), 3.07 - 3.20 (m, 1 H), 3.31 - 3.52 (m, 5 H), 3.78 (dd, J=1 1.4, 1.8 Hz, 1 H), 3.99 (dd, 25 J=11.4, 2.2 Hz, 1 H), 4.04 - 4.14 (m, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.66 (t, J=5.7 Hz, 1 H), 4.79 - 5.02 (m, 2 H), 7.07 (dd, J=10.4, 8.6 Hz, 1 H), 7.15 - 7.25 (m, 1 H), 7.28 - 7.37 (m, 1 H), 8.42 (s, 1 H), 9.50 (t, J=6.2 Hz, 1 H). Example 75 rac-N-(3-Cyclopropyl-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 30 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 161 WO 2009/016498 PCT/IB2008/002046 F N' N, O NH O OH 1N 0 N Step 1: Preparation of ethyl 3-cyclopropvl-4-fluorobenzoate F 0 Cyclopropylmagnesium bromide (2.0 M in ether, 137.61 mL, 275.23 mmol) was added slowly 5 to a solution of anhydrous ZnCl 2 (37.43 g, 275.23 mmol) in dry tetrahydrofuran (200 mL) under an argon atmosphere. The resulting white slurry was stirred at 50 *C for 3 h. In a separate flask a solution of ethyl 3-bromo-4-fluorobenzoate (prepared as described in step 1 of the synthesis of N-(3-ethyl-4 fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 49) (17 g, 68.80 mmol) in dry tetrahydrofuran (150 mL) was sequentially treated with 10 PdCl 2 (dppf) (2.8 g, 3.44 mmol) and copper(l) iodide (0.78 g, 4.12 mmol) under an argon atmosphere. The alkyl zinc slurry was added to the ester mixture at room temperature. The resulting brown slurry was stirred in the dark at room temperature for 48 h. The reaction mixture was concentrated under vacuum to give a dark brown residue, which was taken up in ethyl acetate (750 mL) and washed sequentially with 1N hydrochloric acid (300 mL) solution, sat. NaHCO 3 solution and brine. The ethyl 15 acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a mixture of the desired product and bromo starting material (9.8 g of - 40/60 product/starting material ). The mixture was carried on to the next step without further purification. Step 2: Preparation of 3-cyclopropyl-4-fluorobenzoic acid F OH 0 20 A mixture containing ethyl 3-cyclopropyl-4-fluorobenzoate from step 1 (16 g) and lithium hydroxide monohydrate (9.68 g, 230.54 mmol) were taken up in a mixture of dioxane/water (1/1, 300 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1N hydrochloric acid under ice-water cold condition. The mixture was extracted with dichloromethane (2 x 150 mL). The combined organic layers were washed 25 with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound contaminated by 3-bromo-4-fluorobenzoic acid (12.0 g). 162 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of 3-cyclopropyl-4-fluorobenzamide F
NH
2 0 A mixture containing 3-cyclopropyl-4-fluorobenzoic acid from step 2 (10.5 g) was taken up in SOC1 2 (150 mL) and then refluxed for 4 h. The SOC1 2 was removed under reduced pressure and the 5 residue was dissolved in dry acetonitrile (125 mL). Ammonia gas was passed through solution at -78 *C for 10 min. The reaction mixture was allowed to warm at room temperature very slowly and stirred overnight. The reaction mixture was concentrated to a residue and extracted with dichloromethane (2 x 100 mL). The combined dichloromethane layers were washed with sat. NaHCO 3 solution followed by brine, dried over sodium sulfate, and concentrated, The crude product was washed with hexane (2 x 10 25 mL) to afford a mixture of the title compound and 3-bromo-4-fluorobenzamide and bromo impurity (9.5 g). Step 4: Preparation of (3-cyclopropyl-4-fluorophenyl)methanamine F) ::- NH 2 Borane dimethylsulfide complex (94%, 21.70 mL, 212.05 mmol) was added slowly to a 15 solution of the mixture containing 3-cyclopropyl-4-fluorobenzamide from step 3 (9.5 g) in dichloromethane (200 mL) under ice-cold condition. After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h. The reaction mixture was cooled to 0 *C, washed with NaHCO 3 solution followed by brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography 20 over silica gel (100-200 mesh) using 25 % CH 2 0 2 in hexane as an eluent to afford the title compound (1.8 g). MS (ES+) m/z 166 (M+H). Step 5: Preparation of rac-N-(3-cyclopropyl-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-14 dioxan-2-yl)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F "N -N, N O N NH -O OH \ /N 0 N 25 A mixture of rac-methyl 6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 67) (100 mg, 0.285 mmol), (3-cyclopropyl 4-fluorophenyl)methanamine (141 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 30 *C for 18 hours. The title compound was isolated as a solid by reverse phase preparative HPLC (58 163 WO 2009/016498 PCT/IB2008/002046 mg, 42%). MS (ES+) m/z 484 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.60 - 0.75 (m, 2 H), 0.95 (d, J=10.3 Hz, 2 H), 1.91 - 2.07 (m, 1 H), 2.81 (s, 3 H), 3.18 - 3.46 (m, 5 H), 3.76 (d, J=1 1.4 Hz, 1 H), 3.97 (d, J=1 1.4 Hz, 1 H), 4.03 - 4.14 (m, 1 H), 4.45 (d, J=6.2 Hz, 2 H), 4.70 - 4.79 (m, 1 H), 4.78 - 4.97 (m, 2 H), 6.94 - 7.10 (m, 2 H), 7.10 - 7.20 (m, 1 H), 8.39 (s, 1 H), 9.47 (t, J=6.0 Hz, 1 H). 5 Example 76 rac-N-(3-Cyano4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F NC N N N O N O OH 0 N Step 1: Preparation of 2-fluoro-5-(hydroxymethyl)benzonitrile F F( -. OH 10 NC 2-fluoro-5-formylbenzonitrile (7.0 g, 46.93 mmol) was dissolved in a mixture of methanol (30 mL) and dichloromethane (20 mL). Solid NaBH 4 (1.8 g, 46.93 mmol) was added portion-wise, and the mixture was stirred at room temperature overnight. The organic volatile was removed and the residue was dissolved in water (50 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic 15 layer was washed with saturated sodium bicarbonate solution followed by brine solution, dried over anhydrous sodium sulfate, and concentrated to afford the title compound (6.6 g, 93 %). Step 2: Preparation of 5-(aminomethyl)-2-fluorobenzonitrile N NH 2 2-fluoro-5-(hydroxymethyl)benzonitrile (6.6 g, 43.66 mmol) was dissolved in dichloromethane 20 (75 mL), and triethylamine (12 mL) was added. Mesityl chloride (4.4 mL, 56,76 mmol) was added drop-wise under ice-cold condition and the reaction mixture was stirred for 2 h at room temperature. The mixture was poured into cold water (50 mL). The organic layer was separated and was washed with saturated aqueous sodium bicarbonate solution, 1% aqueous hydrochloric acid solution and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, The residue 25 was dissolved in acetonitrile (50 mL), and aqueous NH 4 0H (30 mL) was added to it. The reaction mixture was stirred at room temperature for 3 h and was then concentrated under reduced pressure. The crude product was purified by washing with hexane and then with ethyl acetate to afford the title compound as a solid (6.8 g, quantitative), 164 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of rac-N-(3-cyano-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan 2-yl)meth yl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F NC N N NCN NH O ,OH \ N 0 N A mixture of rac-methyl 6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 5 tetrazol-5-yl)-2-methylpyrimidine-4-carboxylate (prepared as described in step 1 of the synthesis of rac-N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 67) (100 mg, 0.285 mmol), 5 (aminomethyl)-2-fluorobenzonitrile (129 mg, 0.856 mmol), and dimethylacetamide (1 mL) was heated to 85 *C for 18 hours. The title compound was isolated as a solid by reverse phase preparative HPLC 10 51 mg, 38%). MS (ES+) m/z 469 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.54 (s, 1 H), 2.84 (s, 3 H), 3.29 - 3.51 (m, 4 H), 3.78 (dd, J=11.7, 2.2 Hz, 1 H), 3.99 (dd, J=11.35, 2.56 Hz, 1 H), 4.03 - 4.14 (m, 1 H), 4.56 (d, J=6.6 Hz, 2 H), 4.65 (t, J=5.5 Hz, 1 H), 4.80 - 5.01 (m, 2 H), 7.49 (t, J=9.2 Hz, 1 H), 7.72 - 7.83 (m, 1 H), 7.88 (dd, J=5.9, 2.2 Hz, 1 H), 8.41 (s, 1 H), 9.63 (t, J=6.2 Hz, 1 H). Example 77 15 rac-N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F HO 0 N'N O NH -O OH O N N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-(2 20 hydroxyethoxy)benzyl)-6-(2-(((trans-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 27) (491 mg, 1.32 mmol), rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2 yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3 methoxybenzyl)-6- (2-(((2S*,5R*)-5-(hydroxymethyl)- 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 61) (398 mg, 1.32 mmol) and 1,8-diazabicyclo[5.4.0]undec 25 7-ene (240 mg, 1.58 mmol) were combined in dimethylacetamide (5 mL). After heating the reaction at 90 *C for 18 h, the reaction mixture was purified by reverse phase preparative high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil which solidified under reduced pressure to give the title compound as an white solid (70 mg, 11%). MS (ES+) m/z 504. 1 H NMR (400 MHz, DMSO-d 6 ) 30 6 ppm 9.48 (s, 1 H), 8.40 (s, 1 H), 7.14 (m, 2 H), 6.89 (m, 1 H), 4.74 (m, 2 H), 4.62 (m ,1 H), 4.41 (m , 165 WO 2009/016498 PCT/IB2008/002046 2 H), 4.15 (m, 1 H), 4.02 (m. 2 H), 3.91 (m, 1 H), 3.78 - 3.95 (m, 2 H), 3.59 - 3.72 (m, 1 H), 3.72 (m, 1 H), 3.61 (m, 2 H), 3.65-3.79 (m, 4 H), 2.81 (s, 3 H). Example 78 rac-N-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 5 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F ClN'N'N'-",O Cl N NH - OH /N O N rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (224 mg, 10 0.741 mmol) was added to a mixture of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4 fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (200 mg, 0.575 mmol) and triethylamine (349 mg, 3.4 mmol) in anhydrous dimethylacetamide (0.3 mL). The reaction was stirred overnight at 85 *C in a capped vial. The mixture 15 was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a carbonate resin column and concentrated. The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (95 mg). MS (ES+) m/z 478 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.60 (1 H, t, J=6.2 Hz), 8.41 (1H,s), 7.57 (1 H, d, J=7.0 Hz), 7.37 (2 H, d, J=7.7 Hz), 4.93 (1 H, d, J=3.7 Hz), 4.88 20 (1 H, d, J=8.1 Hz), 4.66 (1 H, br. s.), 4.52 (2 H, d, J=6.2 Hz), 4.08 (1 H, d, J=2.9 Hz), 3.99 (1 H, d, J=11.3 Hz), 3.78 (1 H, d, J=9.9 Hz), 3.36 - 3.48 (2 H, m), 3.45 (3 H, t, J=10.8 Hz), 3.30 - 3.34 (1 H, m), 2.84 (3 H, s). Example 79 N-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 25 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F Cl - N NH O OH N 0 N ((2R,5R)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-m ethylpyrim idine-4-carboxam ide, Example 62) (136 mg, 0.45 166 WO 2009/016498 PCT/IB2008/002046 mmol) was added to a mixture of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine 4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-2 methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (125 mg, 0.359 mmol) and triethylamine (153 mg, 1.5 mmol) in anhydrous dimethylacetamide (0.3 mL). The 5 reaction was stirred overnight at 85 *C in a capped vial. The mixture was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a carbonate resin column and concentrated. The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (49 mg). MS (ES+) m/z 478 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.60 (1 H, t, J=6.2 Hz), 8.41 (1 H,s), 7.57 (1 H, d, 10 J=7.0 Hz), 7.37 (2 H, d, J=7.7 Hz), 4.93 (1 H, d, J=3.7 Hz), 4.88 (1 H, d, J=8.1 Hz), 4.66 (1 H, br. s.), 4.52 (2 H, d, J=6.2 Hz), 4.08 (1 H, d, J=2.9 Hz), 3.99 (1 H, d, J=1 1.3 Hz), 3.78 (1 H, d, J=9.9 Hz), 3.36 - 3.48 (2 H, m), 3.45 (3 H, t, J=10.8 Hz), 3.30 - 3.34 (1 H, m), 2.84 (3 H, s). Example 80 N-(3-Bromo-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 15 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F Br N O O NH o OH O N Step 1: Preparation of N-(3-bromo-4-fluorobenzvl)-2-methyl-6-(2H-tetrazol-5-vl)pvrimidine-4 carboxamide 0 N Br ,NH [ O N'N B N N N 20 3-Bromo-4-fluorobenzylamine (865 mg, 3.6 mmol) was added to a solution of methyl 2-methyl 6-(2H-tetrazol-5-yl)pyrimidine-4-carboxylate (229 mg, 1.04 mmol) (prepared as described in step 1 of the synthesis of N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-acetamidocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 17) and triethylamine (316 mg, 3.1 mmol) in anhydrous dimethylacetamide (2.0 mL). The mixture was stirred at 65 *C for 2.5 days. After 25 cooling to room temperature, the reaction mixture was diluted with excess 2.5 N NaOH solution and washed with ethyl acetate (2x). The aqueous layer was acidified with concentrated hydrochloric acid, The resulting precipitate was filtered, washed with water, and dried to afford the title compound as a light yellow solid (300 mg). 167 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(3-bromo-4-fluorobenzvl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yI)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F Br N'N'N/' O NH - OH N O N ((2R,5R)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as 5 described in step 1 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 62) (136 mg, 0.45 mmol) was added to a mixture of N-(3-bromo-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine 4-carboxamide (125 mg, 0.359 mmol) and triethylamine (153 mg, 1.5 mmol) in anhydrous dimethylacetamide (0.3 mL). The reaction was stirred overnight at 85 *C in a capped vial, The mixture 10 was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing product were neutralized by passing through a carbonate resin column and concentrated. The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (61 mg). MS (ES+) m/z 522 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.60 (1 H, t, J=6.0 Hz), 8.41 (1 H, s), 7.69 (1 H, d, J=5.5 Hz), 7.41 (1 H, d, J=1.8 Hz), 7.33 (1 H, t, J=8.8 Hz), 4.93 15 (1 H, d, J=3.7 Hz), 4.88 (1 H, d, J=8.1 Hz), 4.66 (1 H, br. s.), 4.52 (2 H, d, J=6.2 Hz), 4.08 (1 H, d, J=2.9 Hz), 3.99 (1 H, d, J=1 1.3 Hz), 3.78 (1 H, d, J=9.9 Hz), 3.36 - 3.48 (2 H, m), 3.45 (2 H, t, J=10.8 Hz), 3.31 (1 H, br. s.), 2.84 (3 H, s). Example 81 N-(4-Fluoro-3-hydroxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H 20 tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide F HO N ' 'O -- N NH -CO OH / N O N N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 65) (476 mg, 1.0 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to -70 *C. A solution of 25 boron tribromide (4.0 mL, 1.0 M in dichloromethane, 4.0 mmol) was added. After 30 min, the mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into a mixture of ice and saturated aq. sodium bicarbonate. The mixture was extracted with dichloromethane (2 x 50 mL). The aqueous layer was acidified to pH 2 with 1 N hydrochloric acid and extracted with dichloromethane (50 mL). The combined organic layers were dried (sodium sulfate) 30 and concentrated. The residue was purified by silica gel column chromatography 168 WO 2009/016498 PCT/IB2008/002046 (dichloromethane/methanol, 100/2; 100/3; 100/4) to afford the title compound as a foaming white solid (114 mg, 25%). MS (ES+) m/z 460 (M+H). 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.72 (s, 1 H), 9.50 (t, J=6.4 Hz, 1 H), 8.37 (s, 1 H), 7.00 (dd, J=1 1.3, 8.4 Hz, 1 H), 6.89 (dd, J=8.6, 2.1 Hz, 1 H), 6.72 6.68 (m, 1 H), 4.89 (dd, J=14.3, 3.7 Hz, 1 H), 4.84 - 4.77 (m, J=14.3, 8.0 Hz, 1 H), 4.65 (t, J=5.7 Hz, 1 5 H), 4.37 (d, J=6.4 Hz, 2 H), 4.06 - 3.98 (m, 1 H), 3.93 (dd, J=1 1.5, 2.3 Hz, 1 H), 3.72 (dd, J=1 1.5, 2.5 Hz, 1 H), 3.42 - 3.18 (m, 5 H), 2.78 (s, 3 H). Example 82 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yI)-2-methylpyrimidine-4-carboxamide F 0_ N 'N H OH N N O'N 10 Step 1: Preparation of (2R)-1 -(benzyloxy)-3-chloropropan-2-ol HO H O K CI To a flame-dried, three neck round bottomed flask was added dry 1,2-dichloroethane (50 mL) and charged with R-(-)-epichlorohydrin (3.8 mL, 49 mmol) and benzyl alcohol (10 mL, 100 mmol). The 15 solution was cooled to 0 *C under nitrogen. The stirring solution was then treated with boron trifluoride etherate (0.27 mL, 2.2 mmol) dropwise and allowed to warm to room temperature overnight. The reaction mixture was then heated to reflux. After about 2 hours, the mixture was cooled to room temperature. The mixture was partitioned against 10% aqueous saturated sodium bicarbonate (25 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 25 mL). 20 The organic layers were combined and washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a viscous oil. The oil was adsorbed onto silica and purified by silica column chromatography eluting with 20-30% ethyl acetate in heptanes to provide the title compound as a viscous oil (5.6 g, 57%). LCMS (5%-100% CH 3
CN/H
2 0, 5 min) 2.7 min, m/z 223 (M+Na). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 7.29 - 7.41 (m, 5 H), 4.58 (s, 2 H), 3.98 25 4.07 (m, 1 H), 3.58 - 3.71 (m, 4 H), 2.49 (d, J=5.8 Hz, 1 H). 169 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of (2S)-3-((1R)-2-(benzvloxy)-1-(chloromethvl)ethoxy)-2-hydroxvpropyl 4 methylbenzenesulfonate O 9
H
0 O' HO' H,O To a flask containing (2R)-1-(benzyloxy)-3-chloropropan-2-ol (2.5 g, 12.5 mmol) was added S 5 glycidol tosylate (0.95 g, 0.33 mmol) and back-filled with nitrogen. The flask was charged with dry 1,2 dichloroethane (50 mL) and the resulting stirring solution cooled to 0 *C. The mixture was treated with boron trifluoride etherate (0.10 mL, 0.81 mmol) dropwise and the reaction mixture was allowed to slowly warm to room temperature overnight. The mixture was diluted with dichloromethane (50 mL) and partitioned against 10% aqueous saturated sodium bicarbonate (100 mL). The layers were 10 separated and the aqueous phase extracted with dichloromethane (2 x 50 mL). The organic layers were combined and washed with water (25 mL) and brine (25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a viscous oil. The oil was adsorbed onto silica and purified by silica column chromatography eluting with 30-50% ethyl acetate in heptanes to provide the title compound as a viscous oil (0.80 gm, 45%). LCMS (5%-100% 15 CH 3
CN/H
2 0, 5 min) 4.0 min, m/z 429 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 7.80 (d, J=8.2 Hz, 2 H), 7,28 - 7.41 (m, 7 H), 4,54 (s, 2 H), 4.02 - 4,13 (m, 2 H), 3.69 - 3.76 (m, 2 H), 3.50 - 3.65 (m, 6 H), 2.95 (d, J=4.3 Hz, 1 H), 2.45 (s, 3 H). Step 3: Preparation of ((2R,5R)-5-((benzyloxy)methyl)-1,4-dioxan-2-vl)methanol 0 OH 0 ,, 0 0 20 To a flask containing (2S)-3-((1 R)-2-(benzyloxy)- 1 -(chloromethyl)ethoxy)-2-hydroxypropy 4 methylbenzenesulfonate (0.80 g, 1.9 mmol) was added 2.5 N aqueous sodium hydroxide solution (2.6 mL, 6.5 mmol). The resulting bi-phasic reaction mixture was vigorously stirred at room temperature. After about 2.5 hours, the reaction mixture was heated to 90 *C. After about 4 hours, the reaction mixture was cooled to room temperature and stirred overnight. The mixture was then re-heated to 90 25 *C for about 2 hours and finally cooled to room temperature. The reaction was neutralized with 1 N hydrochloric acid and solid sodium chloride was added to saturation. The reaction mixture was partitioned against dichloromethane (10 mL). The aqueous layer was extracted with additional portions of dichloromethane (3 x 10 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated under 30 reduced pressure to give a viscous oil. The oil was purified by silica column chromatography eluting with 1-4% methanol in dichloromethane to provide the title compound as a viscous oil (0.20 gm, 45%). LCMS (5%-100% CH 3
CN/H
2 0, 5 min) 2.6 min, m/z 239 (M+H). H NMR (400 MHz, CDC 3 ) 6 ppm 7.25 - 7.45 (m, 5 H), 4.59 (s, 2 H), 3.5 - 3.9 (m, 10 H), 2.3 (br. S., 1 H). 170 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of ((2S,5R)-5-((benzvloxy)methyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate 0O O To a solution of ((2R,5R)-5-((benzyloxy)methyl)-1,4-dioxan-2-yl)methanol (0.20 g, 0.59 mmol) 5 in pyridine (3 mL) was added p-toluenesulfonyl chloride (0.38 g, 3.4 mmol) and a small crystal of 4 dimethylaminopyridine. The reaction mixture was left to stir at room temperature overnight. The mixture was then treated with additional p-toluenesulfonyl chloride (0.10 gm) and left to stir for about 8 hours. The reaction mixture was treated with toluene (10 mL) and concentrated under reduced pressure using a cold bath. The addition of toluene and concentration under reduced pressure was 10 repeated (3x). The resulting residue was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). The organic phases were combined and washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a viscous oil. This oil was adsorbed onto silica and purified by silica column chromatography eluting with 30-40% 15 ethyl acetate in heptanes to provide the title compound as a viscous oil (0.19 gm, 82%). LCMS (50% 100% CH 3
CN/H
2 0, 5 min) 2.6 min, m/z 393 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 7.81 (d, J=8.2 Hz, 2 H), 7.28 - 7.41 (m, 7 H), 4.54 (s, 2 H), 4.30 (dd, J=10.4, 7.0 Hz, 1 H), 4.12 (dd, J=10.4, 5.6 Hz, 1 H), 3.52 - 3.86 (m, 7 H), 3.42 - 3.50 (m, 1 H), 2.45 (s, 3 H). Step 5 Preparation of ((2S.5R)-5-(hydroxvmethyl)-1,4-dioxan-2-vl)methyl 4-methylbenzenesulfonate HO.QO 20 To a solution of ((2S,5R)-5-((benzyloxy)methyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (0.19 g, 0.48 mmol) in ethanol (5 mL) under nitrogen was added palladium on carbon and back-filled with hydrogen gas. The mixture was allowed to stir at room temperature overnight under a balloon of hydrogen gas. The reaction mixture was filtered through CeliteTm with 25 ethanol washes. The combined filtrates were concentrated under reduced pressure to give the title compound as a viscous oil (0.13 gm, 89%). LCMS (5%-100% CH 3
CN/H
2 O, 5 min) 2.8 min, m/z 303 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 7.80 (d, J=8.2 Hz, 2 H), 7.35 (d, J=8.2 Hz, 2 H), 4.21 - 4.30 (m, 1 H), 4.11 - 4.19 (m, 1 H), 3.76 - 3.85 (m, 1 H), 3.52 - 3.75 (m, 7 H), 2.45 (s, 3 H). 171 WO 2009/016498 PCT/IB2008/002046 Step 6: Preparation of N-(4-fluoro-3-methoxvbenzvl)-6-(2-(((2R,5R)-5-(hydroxvmethyl)-1,4-dioxan-2 vl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F O N N%_ OHO N 0 O /,N 0 To a vial containing N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine- 4 5 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 (trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (101 mg, 0.29 mmol) and ((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)m ethyl 4 methylbenzenesulfonate (115 mg, 0.38 mmol) was added N,N-dimethylformamide (0.3 mL) followed by triethylamine (1.0 mL). The vial was flushed with nitrogen, tightly capped and heated to 85 *C with 10 stirring. After about 2 days, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (10 mL) and partitioned with water (10 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The organic layers were combined and washed with 1 N hydrochloric acid solution (10 mL), water (10 mL), 1 N sodium hydroxide solution (10 mL), water (10 mL), brine, 15 dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica column chromatography eluting with 1-3% methanol in ethyl acetate. The crude product was further purified by reverse phase preparative HPLC (acetonitrile/water) to provide the title compound as a white solid (39 mg, 28%). LCMS (5%-100% CH 3
CN/H
2 0, 5 min) 3.05 min, m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.58 (t, J=6.4 Hz, 1 H), 8.42 (s, 1 H), 7.09 - 7.24 (m, 2 20 H), 6.83 - 6.96 (m, 1 H), 5.35 (dd, J=14.2, 9.9 Hz, 1 H), 4.98 (dd, J=14.3, 4.0 Hz, 1 H), 4.70 - 4.82 (m, 1 H), 4.50 (d, J=6.3 Hz, 2 H), 4.16 - 4.28 (m, I H), 3.82 (s, 3 H), 3.73 - 3.81 (m, 3 H), 3.43 - 3.58 (m, 4 H), 2.83 (s, 3 H). Example 83 N-(3-Chloro-4-fluorobenzyl)-6-(2-((5,5-bis(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5 25 yl)-2-methylpyrimidine-4-carboxamide F N N OH0 Cl OH N N/ .'N O OH 172 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of trans-(5-formyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 0 H /\S-Os 0 0 To a -78 0C solution of oxalyl chloride (6.43 g, 49.6 mmol) in dichloromethane (30 mL) was slowly added dimethyl sulfoxide (7.29 g, 93.3 mmol). The reaction was stirred at -78 0C for 20 min at 5 which time a solution of rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3 methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 61) (6.0 g, 20 mmol) in dichloromethane (12 mL) was added drop-wise. The resulting solution was stirred at -78 0C for 1h and then quenched with 10 triethylamine (11.0 g, 109 mmol) forming a thick white precipitate. The ice bath was removed and the reaction was slowly warmed to room temperature. The mixture was diluted in dichloromethane (100 mL) and washed successively with 1N hydrochloric acid (75 mL), sat. sodium bicarbonate (75 mL), and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a yellow oil (6.4 g, 100%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.43 (s, 1 15 H), 7.75 (m, 2 H), 7.47 (m, 2 H), 3.63 - 4.08 (m, 5 H), 3.17 - 3.38 (m, 3 H), 2.39 (s, 3 H), Step 2: Preparation of (5,5-bis(hydroxymethyl)-1,4-dioxan-2-vI)methyl 4-methylbenzenesulfonate HO 0 'C' OH s-O 0 0 2.5 N Sodium hydroxide (17.0 mL, 1.70 g, 42.6 mmol) was added to a solution of trans-((5 formyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (6.4 g, 21.0 mmol) in 2:1 20 tetrahydrofuran/water (30 mL). To this reaction was added a 37% solution of formaldehyde (3.69 mL, 3.80 g, 46.9 mmol) and the mixture was stirred at 25 0C for 18 hours. The reaction mixture was neutralized with formic acid (2 mL). The reaction was concentrated, washed with ethyl acetate (150 mL) and filtered. The filtrate was concentrated to afford the title compound as a yellow oil that solidified upon standing (5.4 g, 76%). LC/MS (5%-95% CH 3
CN:H
2 0, 6 min): 3.69 min, m/z 333 (M+H). 25 'H NMR (400 MHz, CDCl 3 ) 6 ppm 7.75 (m, 2 H), 7.33 (m, 2 H), 4.75 (m, 2 H), 3.95 - 3.49 (m, 3 H), 3.45 - 3.75 (m, 9 H), 2.43 (s, 3 H). 173 WO 2009/016498 PCT/IB2008/002046 Step 3: N-(3-chloro-4-fluorobenzyl)-6-(2-((5,5-bis(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol 5-yl)-2-methylpyrimidine-4-carboxamide F N0 Cl N O OH N N 'O OH N-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared 5 as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin-2 ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (50 mg, 0.144 mmol), (5,5 bis(hydroxymethyl)- 1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (47.8 mg, 0.144 mmol), and triethylamine (400 pL) were combined in dimethylacetamide (100 pL). The resulting mixture was stirred at 90 *C for 18 h. The mixture was concentrated. The residue was purified by reverse phase 10 high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (12 mg, 16%). MS (ES+) m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.61 (t, J = 6.2 Hz, 1 H), 7.57 d, J = 7.0 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 2 H), 4.97 (s, 1 H), 4.95 (d, J = 3.3 Hz, 1 H), 4.44 4.54 (m, 1 H), 4.52 (d, J = 6.2 Hz, 3 H), 3.73 (d, J = 3.3 Hz, 1 H), 3.60 (t, J = 5.5 Hz, 1 H), 3.66 (m, 2 15 H), 3.39 (d, J = 4.4 Hz, 1 H), 3.35 - 3.44 (m, 1 H), 3.23 (s, 1 H), 3.25 (d, J = 5.5 Hz, 2 H), 2.84 (s, 3 H), 2.74 (s, 1H). Example 84 N-(3-Methoxybenzyl)-6-(2-((5,5-bis(hydroxym ethyl) -1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide HN_0 -0 OH N -O N~ NN OH N N' O OH 20 N-(3-Methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide(prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (47 mg, 0.144 mmol), (5,5 bis(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 25 of the synthesis of N-(3-chloro-4-fluorobenzyl)-6-(2-((5,5-bis(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 83) (48 mg, 0.144 mmol), and triethylamine (400 pL) were combined in dimethylacetamide (100 pL). The resulting mixture was stirred at 90 *C for 18 h. The mixture was concentrated and the residue was purified by reverse phase high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate 30 (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (12 mg, 16%). MS (ES+) m/z 486 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.49 (m, 1 H), 8.42 (s, 174 WO 2009/016498 PCT/IB2008/002046 1 H), 7.24 (m, 1 H), 6.93 (m, 2 H), 6.81 (m, 2 H), 4.96 (m, 2 H), 4.53 (m, 3 H), 4.18 (m, 2 H), 3.74 (s, 3 H), 3.48 - 3.62 (m, 4 H), 3.42 (m, 2 H), 2.86 (s, 3 H). Example 85 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol 5 2-yl)methyl)-1,4-dioxane-2-carboxylate - HN N 0 O N N-N o Step 1: Preparation of trans-1,4-dioxane-2,5-dicarboxylic acid HO 0 0 O 0 OH A solution of trans-2,5-bis-(hydroxymethyl)-1,4-dioxane (prepared as described in step 3 of the 10 synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (88.17 g) in water (458 mL) and HNO 3 (1238 mL) was heated to reflux for 100 min and then cooled to 5 *C. The resulting precipitate was collected by filtration, washed with cold water (500 mL), and dried in vacuo at 50 0C overnight to provide the title compound (100.75 g). 15 Step 2: Preparation of trans-dimethyl 1,4-dioxane-2,5-dicarboxylate -O 0 0 O 0 0 trans-1,4-Dioxane-2,5-dicarboxylic acid (90 g) was dissolved in hot methanol (1380 mL). The solution was cooled to 15 *C and HCI gas (approximately 45 g) was bubbled through the solution until saturated. The reaction mixture was stirred at room temperature for 24 hours, and then cooled to 5 *C. 20 The resulting precipitate was collected by filtration, washed methanol and cold saturated sodium bicarbonate solution (500 mL). The solid was further washed with cold water (500 mL) until the wash was neutral. The product was dried in a vacuo at 50 *C overnight to afford the title compound (97 g). Step 3: Preparation of rac-(2R*,5S*)-5-(methoxycarbonyl)-1,4-dioxane-2-carboxylic acid HO 0 0 25 A solution of trans-dimethyl 1,4-dioxane-2,5-dicarboxylate (68.54 g, 336 mmol) in methanol (3.2 L) and water (0.8 L) was slowly added to a solution of lithium hydroxide monohydrate (10.56 g, 252 mmol) in water (0.6 L). The reaction mixture was maintained at 20 *C during the addition by applying a water bath. The resulting solution was stirred for 24 h and concentrated to remove most of the methanol in vacuo. The remaining aqueous mixture was extracted with ethyl acetate (2 L). The 30 aqueous layer was then acidified to pH 2 with 6 N hydrochloric acid and concentrated to a small 175 WO 2009/016498 PCT/IB2008/002046 volume (ca. 400 mL). The mixture was cooled to 0-5 *C and filtered. The solids were washed with cold water and dried in a vacuum oven at 50 *C for 24 h to afford the title compound (33.34 g). Step 4: Preparation of rac-(2S*,5S*)-methyl 5-(hydroxymethyl)-1,4-dioxane-2-carboxylate HO 0 0 0 0 5 rac-(2R*,5S*)-5-(Methoxycarbonyl)-1,4-dioxane-2-carboxylic acid (19.34 g, 102 mmol) was dissolved in tetrahydrofuran (800 mL). A solution of borane dimethylsulfide (10 M, 12.2 mL) was slowly added to the solution. The mixture was stirred at room temperature for 3 h and then quenched with water (50 mL). The mixture was concentrated under vacuum. The residue was suspended in ethyl acetate and filtered. The filtrate was concentrated. The residue was again suspended in chloroform, 10 filtered, and the filtrate concentrated. The crude product was purified by silica gel chromatography (dichloromethane/methanol, 99.5/0.5 - 98/2) to afford the title compound. Step 5: Preparation of rac-(2S*,5R*)-methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate 0 S-a 0 0 OOO 0 0 p-Toluene sulfonylchloride (3.46 g, 18.15 mmol) was added portion-wise over 30 min to a 15 solution of rac-(2S*,5S*)-methyl 5-(hydroxymethyl)-1,4-dioxane-2-carboxylate (3.2 g, 18.0 mmol) in anhydrous pyridine (24 mL). The mixture was stirred at room temperature for 3.5 h. Water (100 mL) was added drop-wise at ice bath temperatures. The resulting precipitate was filtered, washed with water, and dried to afford the title compound as a white solid (4.31 g). Step 6: Preparation of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxvbenzl)carbamovl)-2-methylPyrimidin 20 4-vl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2-carboxylate - N O 0 -O N ' N O N N - N O rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)- 1,4-dioxane-2-carboxylate (2.19 g, 6.6 mmol) was added to a solution of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 25 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyriniidine-4-carboxamide, Example 5) (2.16 g, 6.6 mmol) and triethylamine (1.33 g, 13.2 mmol) in anhydrous dimethylacetamide (4 mL). The mixture was stirred at 85 *C in a capped vial overnight. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (54 mg). 176 WO 2009/016498 PCT/IB2008/002046 Example 86 rac-(2S*,5S*)-5-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methylpyrim idin-4-yl)-2H-tetrazol-2 yl)methyl)-1,4-dioxane-2-carboxylic acid -0 / N \ N , N O OH N N'NN -N 5 Sodium hydroxide (10 pellets) was added to a mixture of rac-(2S*,5S*)-methyI 5-((5-(6-((3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol- 2 -yl)methyl)- 1,4-dioxane-2-carboxylate (54 mg) in tetrahydrofuran (3 mL) and water (3 mL). The mixture was stirred overnight at room temperature. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were concentrated. The 10 residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (736 mg). MS (ES+) m/z 470 (M+H). 1H NMR (400 MHz, DMSO-d) 6 ppm 9.48 (1 H, t, J=6.2 Hz), 8.42 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.93 (2 H, br. s.), 6.83 (1 H, d, J=7.3 Hz), 4.96 (1 H, d, J=3.3 Hz), 4.92 (1 H, d, J=7.7 Hz), 4.51 (2 H, d, J=6.2 Hz), 4.09 (2 H, t, J=10.4 Hz), 4.12 (1 H, d, J=12.8 Hz), 3.95 (1 H, dd, J= 11.7, 2.6 Hz), 3.74 (3 H, s), 3.49 (2 H, dt, J=16.4, 10.8 Hz), 2.83 15 (3 H, s), 2.43 (1 H, s). Example 87 rac-(2S*,5S*)-methyl 5-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methyipyrimidin-4-yl)-2H tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F N -D H N0 -O /\ NNT OO N0 'N 0 N N N 0 20 rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)- 1 ,4-dioxane-2-carboxylate, Example 85) (562 mg, 1.7 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5 yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3 25 methoxybenzyl)-6-(2-(trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 9) (400 mg, 1.17 mmol) and triethylamine (233 mg, 2.3 mmol) in anhydrous dimethylacetamide (1.0 mL). The mixture was stirred at 85 *C in a capped vial overnight. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (210 mg). 177 WO 2009/016498 PCT/IB2008/002046 Example 88 rac-(2S*,5S*)-5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylic acid F O -P HN 0 -O N N N 0 OH N N'N =N N- 0 5 Sodium hydroxide (2 pellets) was added to a mixture of rac-(2S*,5S*)-methyl 5-((5-(6-((4 fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2 carboxylate (prepared as described in Example 87) (34 mg, 0.068 mmol) in tetrahydrofuran (0.4 mL) and water (0.4 mL). The mixture was stirred overnight at room temperature. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile). 10 Fractions containing the product were concentrated. The residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (31 mg). MS (ES+) m/z 488 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.46 - 9.56 (1 H, m), 8.42 (1 H, s), 7.17 (1 H, dd, J=12.8, 8.8 Hz), 6.92 (1 H, br. s.), 4.89 - 5.00 (2 H, m), 4.50 (2 H, d, J=5.9 Hz), 4.06 (3 H, br. s.), 3.95 (1 H, d, J=11.7 Hz), 3.82 (3 H, s), 3.48 (2 H, dd, J=10.4, 7.5 Hz), 3.22 (2 H, br. s.), 2.83 (2 H, 15 s), 1.25 (2 H, d, J=5.1 Hz) Example 89 (2S,5S)-5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-y)-2H-tetrazol-2 yl)methyl)-1,4-dioxane-2-carboxylic acid F - N NH -O OH N O 0 N 20 A mixture of N-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 65) (238 mg, 0.5 mmol) and pyridinium dichromate (1.15 g, 3.0 mmol) in DMF (5.0 mL) was shaken for 24 hours at room temperature. The reaction mixture was diluted with dichloromethane (50 mL) and washed with 1 N hydrochloric acid solution (2 x 50 mL). The organic layer was extracted with 1 N 25 sodium hydroxide solution (2 x 40 mL). The combined aqueous layers were acidified with concentrated hydrochloric acid and extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated. The residue was triturated with diethyl ether and filtered to afford the title compound as a white solid (79 mg, 32%). MS (ES+) m/z 488 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.58 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 7.17 (dd, J=8.4, 30 2.2 Hz, 1 H), 7.13 (dd, J=1 1.7, 8.4 Hz, 1 H), 6.89 (ddd, J=8.3, 4.5, 2.2 Hz, 1 H), 4.97 (dd, J=14.3, 3.7 178 WO 2009/016498 PCT/IB2008/002046 Hz, 1 H), 4.89 (dd, J=14.3, 7.7 Hz, 1 H), 4.49 (d, J=6.2 Hz, 2 H), 4.15 - 4.03 (m, 3 H), 3.93 (dd, J=11.5, 3.1 Hz, 1 H), 3.81 (s, 3 H), 3.53 - 3.41 (m, 2 H), 2.82 (s, 3 H). Example 90 (2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H 5 tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F 0 NN N ' /0NH - I CK N N O 0 N A mixture of N-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 65) (952 mg, 2.0 mmol) and pyridinium dichromate (4.61 g, 12.0 mmol) in DMF (20.0 mL) was shaken for 10 36 h at room temperature. The reaction mixture was poured into 1 N hydrochloric acid solution (100 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated. The residue was dissolved in methanol (50 mL) and a solution of hydrochloric acid (4M in dioxane, 25 mL) was added. The mixture was allowed to stand for 18 h and was then concentrated. The residue was mixed with dichloromethane (50 mL) and water (100 mL). 15 The aqueous layer was further extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried (sodium sulfate), and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1; 100/2) to afford the title compound (711 mg, 71%). MS (ES+) m/z 502 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 9.58 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 7.17 (dd, J=8.1, 2.2 Hz, 1 H), 7.13 (dd, J=11.3, 8.1 Hz, 1 H), 6.89 20 (ddd, J=8.3, 4.5, 1.8 Hz, 1 H), 4.98 (dd, J=14.3, 3.7 Hz, I H), 4.90 (dd, J=14.3, 7.7 Hz, 1 H), 4.48 (d, J=6.6 Hz, 2 H), 4.24 (dd, J=10.2, 2.9 Hz, 1 H), 4.17 - 4.10 (m, 1 H), 4.08 (dd, J=11.5, 2.7 Hz, 1 H), 3.99 - 3.91 (m, 1 H), 3.81 (s, 3 H), 3.63 (s, 3 H), 3.56 - 3.44 (m, 2 H), 2.82 (s, 3 H). Example 91 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5S)-5-(2-hydroxypropan-2-yl)-1,4-dioxan-2-yl)methyl) 25 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F \ N, N '0 O N O$O NH - ; OH 0 N (2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate (prepared as in Example 90) (251 mg, 0.5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and the solution was cooled to -70 *C. A solution of 179 WO 2009/016498 PCT/IB2008/002046 methylmagnesium bromide (3 M in ethyl ether, 666 pL, 2.0 mmol) was added and the mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with 1 N hydrochloric acid (5 mL). The mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated. The crude 5 product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1; 100/2) to afford the title compound (51.7 mg, 21%). MS (ES+) m/z 502 (M+H). IH NMR (400 MHz, DMSO d) 6 ppm 9.57 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 7.20 - 7.10 (m, 2 H), 6.89 (ddd, J=8.4, 4.4, 2.2 Hz, 1 H), 4.93 (dd, J=13.9, 3.7 Hz, 1 H), 4.88 - 4.82 (in, J=14.3, 7.7 Hz, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.46 (s, 1 H), 4.07 - 3.98 (m, 2 H), 3.85 - 3.77 (m, 4 H), 3.39 (dt, J=16.8, 11.3 Hz, 2 H), 3.19 - 3.13 (m, 10 J=10.2, 2.2 Hz, 1 H), 2.82 (s, 3 H), 1.06 (s, 3 H), 0.99 (s, 3 H). Example 92 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin-4-yl)- 2
H
tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F N 0 -P HN- 0 Cl N" NN O0 N N'N O 15 rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2-carboxylate, Example 85) (244 mg, 0.74 mnol) was added to a solution of N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine 4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-2 20 methyl-6-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 47) (200 mg, 0.575 mmol) and triethylamine (349 mg, 3.4 mmol) in anhydrous dimethylacetamide (0.3 mL). The mixture was stirred at 85 *C in a capped vial overnight. The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (103 mg). Example 93 25 rac-(2S,5S*)-5-((5-(6-((3-Chloro4-fluorobenzyl)carbamoyl)-2-methylpyrimidin4-yl)-2H-tetrazol 2-yl)methyl)-1,4-dioxane-2-carboxylic acid F _ - 0 FHN O 0 Cl Y\ R NN N " NT OOH N NN 0 Sodium hydroxide (3 pellets) was added to a mixture of rac-(2S*,5S*)-methyl 5-((5-(6-((3 chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2 30 carboxylate (prepared as described in Example 92) (103 mg) in tetrahydrofuran (0.4 mL) and water (0.4 mL). The mixture was stirred overnight at room temperature. The reaction mixture was acidified 180 WO 2009/016498 PCT/IB2008/002046 with trifluoroacetic acid with ice bath cooling and purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were concentrated. The residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (88 mg). MS (ES+) m/z 492 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.55 - 9.64 (1 H, m), 5 8.42 (1 H, s), 7.57 (1 H, d, J=7.3 Hz), 7.37 (2 H, d, J=7.0 Hz), 4.91 (1 H, br. s.), 4.95 (1 H, d, J=12.8 Hz), 4.52 (2 H, d, J=5.9 Hz), 4.11 (3 H, d, J=12.8 Hz), 4.06 (1 H, br. s.), 3.95 (1 H, d, J=11.7 Hz), 3.48 (1 H, t, J=1 1.0 Hz), 3.44 - 3.55 (1 H, m), 2.84 (3 H, s). Example 94 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-bromo-4-fluorobenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H 10 tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F P-\0 FHN O Br N NN O N 0 N N'N 0 rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate, Example 85) (150 mg, 0.454 15 mmol) was added to a solution of N-(3-bromo-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine 4-carboxamide (prepared as described in step 1 of the synthesis of N-(3-bromo-4-fluorobenzyl)-6-(2 (((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 80) (150 mg, 0.382 mmol) and triethylamine (153 mg, 1.5 mmol) in anhydrous dimethylacetamide (0.3 mL). The mixture was stirred at 85 *C in a capped vial overnight. The reaction 20 mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (70 mg). Example 95 rac-(2S*,5S*)-5-((5-(6-((3-Bromo4-fluorobenzyl)carbamoyl)-2-methylpyrimidin4-yl)-2H-tetrazol 2-yl)methyl)-1,4-dioxane-2-carboxylic acid F -0 FN O Br NR\ NOH N I OH 25 Sodium hydroxide (3 pellets) was added to a mixture of rac-(2S*,5S*)-methyl 5-((5-(6-((3 brom o-4-fluorobenzyl)carbamoyl)-2i-methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2 carboxylate (prepared as described in Example 94) (70 mg) in tetrahydrofuran (0.4 mL) and water (0.4 mL). The mixture was stirred overnight at room temperature. The reaction mixture was acidified with 30 trifluoroacetic acid with ice bath cooling and purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were concentrated. The residue was slurried and 181 WO 2009/016498 PCT/IB2008/002046 decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (18 mg). MS (ES+) m/z 536 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.61 (1 H, t, J=6.2 Hz), 8.42 (1 H, s), 7.69 (1 H, d, J=7.0 Hz), 7.41 (1 H, t, J=5.7 Hz), 7.33 (1 H, t, J=8.6 Hz), 4.90 - 5.00 (2 H, m), 4.52 (3 H, d, J=6.2 Hz), 4.05 - 4.17 (3 H, m), 3.95 (1 H, dd, J=11.9, 2.7 Hz), 3.50 (2 H, dt, J=16.3, 5 11.1 Hz), 2.84 (3 H, s). Example 96 rac-N-(3-Methoxybenzyl)-6-(2-(((2S*,5R*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide _ NH O NH 2 O N 0 N 10 Step 1: Preparation of rac-((2S*,5S*)-5-((5-(6-((3-methoxvbenzvi)carbamoyl)-2-methylpyrimidin-4-vi) 2H-tetrazol-2-yl)methyl)-1,4-dioxan-2-vl)methyl 4-methylbenzenesulfonate N N 0 N In a 40 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as 15 described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (520 mg, 1.60 mmol) was combined with rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (604 mg, 20 2.00 mmol), polymer supported triphenylphosphine (1490 mg, 3.20 mmol), and anhydrous tetrahydrofuran (15 ml). The reaction mixture was cooled to 0 *C and di-tert-butyl azodicarboxylate (736 mg, 3.20 mmol) was added. The mixture was stirred at 0 *C for 2 hours and then was allowed to warm to room temperature for 12 hours. The reaction mixture was filtered and concentrated to oil. The oil was dissolved in acetonitrile and water and chromatographed by reversed phased preparative 25 HPLC (Gilson prep, Delta Pak column, 30 to 40% acetonitrile, 10 min hold, 40 min run, 10 min hold). Fractions containing the desired were combined and concentrated under vacuum to afford the title compound as a white solid (136.5 mg). 'H NMR (400 MHz, methanol-d 4 ) d ppm 2.84 - 2.86 (m, 3 H), 3.03 (dd, J=13.3, 2.8 Hz, 1 H), 3.37 (dd, J=11.6, 10.2 Hz, 1 H), 3.60 (dd, J=11.6, 10.5 Hz, 1 H), 3.74 3.77 (m, 3 H), 4.12 (dd, J=1 1.7, 2.6 Hz, 1 H), 4.20 - 4.28 (m, 1 H), 4.57 - 4.62 (m, 2 H), 4.87 - 4.90 (m, 30 2 H), 6.81 (dd, J=7.9, 2.0 Hz, 1 H), 6.90 - 6.95 (m, 2 H), 7.22 (t, 1 H), 8.57 (s, 1 H), 9.50 (t, 1 H). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min): 6.47 min, m/z 610 (M+H). 182 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(aminomethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide /0 NNN ONH
NH
2 O N 0
N
In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard 5 pressure, rac-((2S*,5S*)-5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H-tetrazol-2 yl)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (130 mg) was dissolved in dimethyl sulfoxide (5 mL) and ammonium hydroxide (31.5 mg, 0.898 mmol) was added. The mixture was stirred at room temperature for 2 hours and then heated to 80 0C for 12 hours. The reaction mixture was concentrated, dissolved in acetonitrile and water, acidified with acetic acid, and chromatographed by 10 reversed phase preparative HPLC (Gilson, Delta Pak column, 30-60% acetonitrile, 5 min hold, 30 min run, 5 min hold). Fractions containing the desired product were collected and concentrated under vacuum to afford the trifluoroacetic acid salt of the title compound as a clear oil (81.6 mg). 'H NMR (400 MHz, methanol-d 4 ) 6 ppm 2.85 (s, 3 H), 3.03 (dd, J=13.3, 2.8 Hz, 1 H), 3.37 (dd, J=11.4, 10.3 Hz, 1 H), 3.60 (dd, J=11.6, 10.5 Hz, 1 H), 3.76 (s, 3 H), 3.81 (dd, J=11.6, 2.4 Hz, 1 H), 4.12 (dd, J=11.7, 15 2.6 Hz, 1 H), 4.20 - 4.28 (m, 1 H), 4.58 - 4.61 (m, 2 H), 4.87 - 4.90 (m, 2 H), 6.79 - 6.83 (m, 1 H), 6.91 6.95 (m, 2 H), 7.22 (t, J=8.1 Hz, 1 H), 8.57 (s, 1 H), 9.50 (t, J=6.58 Hz, 1 H). LC/MS (5%-95%
CH
3
CN/H
2 0, 5 min): 2.241 min, m/z 455 (M+H). Example 97 rac-N-(3-Methoxybenzyl)-6-(2-(((2S*,5R*)-5-(acetamidomethyl)-1,4-dioxan-2-yl)methyl)-2H 20 tetrazol-5-yl)-2-methylpyri midine-4-carboxamide -- ,N ' -N H NH N-O N \ / N 0 0 N In a 20 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, rac-N-(3-m ethoxybenzyl)-6-(2-(((2 S*,5R*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide trifluoroacetate (prepared as described in Example 25 96) (40 mg, 0.70 mmol) was combined with N,N-dimethylformamide (5 mL) and N,N diisopropylethylamine (59.2 mg, 0.458 mmol). Acetic anhydride (19.1 mg, 0.187 mmol) was added and the mixture was stirred overnight. The reaction mixture was concentrated, re-dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20 60% acetonitrile, 10 min hold, 20 min run, 10 min hold). Fractions containing the desired product were 30 collected and concentrated to afford the title compound as a white solid (21.3 mg). 'H NMR (400 MHz, methanol-d 4 ) 6 ppm 1.32 - 1.37 (m, 2 H), 1.91 (s, 3 H), 2.85 (s, 3 H), 3.09 - 3.16 (m, 1 H), 3.18 - 3.24 183 WO 2009/016498 PCT/IB2008/002046 (m, 1 H), 3.49 - 3.60 (m, 1 H), 3.76 (s, 3 H), 4.01 (dd, J=11.6, 2.4 Hz, 1 H), 4.14 - 4.22 (m, 1 H), 4.58 4.62 (m, 1 H), 6.81 (dd, J=8.1, 1.9 Hz, 1 H), 6.92 - 6.95 (m, 2 H), 7.23 (t, J=8.1 Hz, 1 H), 8.58 (s, 1 H), 9.49 (t, J=6.6 Hz, 1 H). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min) 2.59 min, m/z 497 (M+H). Example 98 5 rac-N-(3-Methoxybenzyl)-6-(2-(((2S*,5R*)-5-(acetamidomethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide 0 N , N 0'~ NH - N H O N N O0 0 N In a 20 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H 10 tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide trifluoroacetate (prepared as described in Example 96) (115 mg, 0.253 mmol) was combined with N,N-dimethylformamide (5 mL) and N,N diisopropylethylamine (98.1 mg, 0.759 mmol) at room temperature. After 30 min, methane sulfonyl chloride was added and the reaction mixture was stirred for 12 hours. The reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phased 15 preparative HPLC (Gilson, Delta Pak column, 30-60% acetonitrile, 10 min hold, 30 min run, 5 min hold). Fractions containing the desired product were collected and concentrated to afford the title compound as a white solid (10 mg). 'H NMR (400 MHz, methanol-d 4 ) 6 ppm 2.68 (s, 3 H), 2.84 (dd, J=13.2, 9.4 Hz, 1 H), 3.03 (dd, J=13.3, 2.6 Hz, 1 H), 3.37 (dd, J=11.6, 10.5 Hz, 1 H), 3.56 - 3.63 (m, 1 H), 3.76 (s, 3 H), 3.82 (dd, J= 11.4, 2.6 Hz, 1 H), 4.11 (dd, J= 11.6, 2.4 Hz, 1 H), 4.18 - 4.26 (m, 1 H), 20 4.60 (s, 2 H), 6.81 (dd, J=9.0, 2.3 Hz, 1 H), 6.91 - 6.96 (m, 2 H), 7.23 (t, J=8.1 Hz, 1 H), 8.11 (d, J=1.1 Hz, 1 H), 8.57 (s, 1 H). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min) 2.695 min, m/z 533 (M+H). Example 99 (-)-N-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2R*,5R*)-5-(hydroxymethyl)-tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F 0- NN NH OH ON 25 184 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of diethyl 2-(but-3-enyl)malonate 0 Small pieces of sodium (13 g, 565 mmol) were added to absolute ethanol (300 mL) slowly. After complete consumption, diethylmalonate (100 g, 625 mmol) was added drop wise. The reaction 5 mixture was heated to 50 0C for 30 min and then cooled to room temperature. 1 -Bromo-3-butene (76 g, 565 mmol) was added and the mixture was refluxed overnight. The ethanol was evaporated and the residue was diluted with water (500 mL). The mixture was extracted with ethyl acetate (3 x 500 mL). The combined ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by vacuum (0.1mm) distillation (bath temp. 125-135 10 *C and vapor temp. 82-85 *C) to afford the title compound (110 g, 82%). Step 2: Preparation of 2-(but-3-enyl)propane-1,3-diol HO OH To a suspension of lithium aluminum hydride (56 g, 1.47 mol) in tetrahydrofuran (800 mL) was added diethyl 2-(but-3-enyl)malonate (80.0 g, 0.373 mol) dissolved in tetrahydrofuran (400 mL) drop 15 wise under ice-water cold condition. Lithium bromide (3.2 g, 37.3 mmol) was added and the mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was cooled in an ice water bath and the reaction was cautiously quenched by the drop-wise addition of water (56 mL), then with 15% aqueous NaOH solution (168 mL) and finally with water (56 mL). The mixture was stirred for another 1 h and filtered. The solid residue was thoroughly washed with tetrahydrofuran (3 x 20 500 mL). The combined filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (41.5 g, 85 %). Step 3: Preparation of (6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol OH To a suspension of iodine (98 g, 386 mmol) and NaHCO 3 (32.6 g, 388.56 mmol) in ether (430 25 mL) and water (205 mL) was added a solution of 2-(but-3-enyl)propane-1,3-diol (33.5 g, 257.33 mmol) in ether (250 mL) at 0 0C. The mixture was stirred at room temperature for 8-10 h and then was quenched by the addition of saturated aqueous Na 2 S20 at 0 *C. The organic layer was separated and the aqueous layer was extracted with ether (2 x 350 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash column 30 chromatography over silica gel (230-400 mesh) using 40% ethyl acetate in hexane as an eluent to afford the title compound as an oil consisting of a mixture of cis/trans isomers (53.0 g, 80.5%). MS (ES+) m/z 256 (M+H). 185 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of (-)-((3R*,6R*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 1) ,, 0 OH An isomeric mixture of (6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (4.0 g) in ethanol (50 mL) was separated by supercritical-fluid chromatography (AD-H 30 x 250 mm, 15% ethanol, 70 5 mL/min, 0.5 mL/injection). The first eluting isomer was isolation and concentrated under vacuum to afford the title compound as a colorless oil (920 mg). 'H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.28 (m, 2 H), 1.50 - 1.64 (m, 1 H), 1.67 - 1.80 (m, 2 H), 2.99 - 3.36 (m, 6 H), 3.89 - 4.00 (m, 1 H), 4.42 (t, J=5.1 Hz, 1 H). SFC (AD-H, 20% ethanol) 3.01 min. LC/MS (5% to 95%, CH 3
CN/H
2 0, 12 min) 4.197 min, m/z 257 (M+H). [a]22A co = -0.380 (acetonitrile, 6.76) 10 Step 5: Preparation of (-)-N-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2R*5R*)-5-(hydroxymethyl)-tetrahydro 2H-pyran-2-vl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F IN', O O N -":,O NH -OH O N In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide 15 (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (600 mg, 1.75 mmol) was dissolved in N,N-dimethyl acetamide (3 mL). N,N-Diisopropylethylamine (226 mg, 1.75 mmol) was added, and the mixture was stirred at room temperature for 30 min. A solution of (-) ((3R*,6R*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 1) (895 mg, 3.50 mmol) in N,N 20 dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 *C for 14 hours. After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20-60% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold). The first eluting peak (49 min) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (373 25 mg). 'H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.14 - 1.25 (m, 1 H), 1.29 - 1.40 (m, 1 H), 1.54 - 1.65 (m, 1 H), 1.78 (d, J=9.9 Hz, 2 H), 2.06 (s, 3 H), 2.82 (s, 3 H), 3.00 (t, J=11.1 Hz, 1 H), 3.14 (dd, J=10.8, 7.20 Hz, 1 H), 3.23 (dd, J=10.7, 5.6 Hz, I H), 3.81 (s, 3 H), 3.86 (dd, J=11.1, 3.9 Hz, 2 H), 4.49 (d, J=6.3 Hz, 2 H), 4.80 - 4.92 (m, 2 H), 6.87 - 6.92 (m, 1 H), 7.10 - 7.20 (m, 2 H), 8.41 (s, 1 H), 9.53 (t, J=6.5 Hz, 1 H). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.748 min, m/z 472 (M+H). HPLC (5%-95% 30 CH 3
CN/H
2 0, 40 min) 19.509 min. [a] = -0.193 (acetonitrile, 0.27) 186 WO 2009/016498 PCT/IB2008/002046 Example 100 (+)-N-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2R*,5R*)-5-(hydroxymethyl)-tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F 0 -N 'N 0 NH - OH \ /N 0
N
5 Step 1: Preparation of (+((3R*,6R*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol Peak 2) ,0 OH The second eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (1.0 g). 1 H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.28 (m, 2 H), 1.50 - 1.64 (m, 1 H), 1.67 - 1.80 (m, 2 H), 2.99 - 3.36 10 (m, 6 H), 3.89 - 4.00 (m, 1 H), 4.42 (t, J=5.1 Hz, 1 H). SFC (AD-H, 20% ethanol) 3.18 min. LC/MS (5% -95%, CH 3
CN/H
2 0, 12 min.) 4.210 min, m/z 257(M+H). [a]22A Co = 0.289 (acetonitrile, 2.56) Step 2: Preparation of (+)-N-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2R*,5R*)-5-(hydroxymethyl) tetrahvdro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F 0 N N O NH -O //N 15 In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (680 mg, 20 1.98 mmol) was dissolved in N,N-dimethyl acetamide (3 mL). N,N-Diisopropylethylamine (256 mg, 1.98 mmol) was added, and the mixture was stirred at room temperature for 30 min. A solution of (+) ((3R*,6R*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 2) (1010 mg, 3.96 mmol) in N,N dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 *C for 14 hours. After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and 25 chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20-60% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold). The first eluting peak (49 min) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (344 mg). 'H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.14 - 1.25 (m, 1 H), 1.29 - 1.40 (m, 1 H), 1.54 - 1.65 (m, 1 187 WO 2009/016498 PCT/IB2008/002046 H), 1.78 (d, J=9.9 Hz, 2 H), 2.06 (s, 3 H), 2.82 (s, 3 H), 3.00 (t, J=11.1 Hz, 1 H), 3.14 (dd, J=10.8, 7.2 Hz, 1 H), 3.23 (dd, J=10.7, 5.3 Hz, 1 H), 3.81 (s, 3 H), 3.86 (dd, J=11.1, 3.9 Hz, 2 H), 4.49 (d, J=6.3 Hz, 2 H), 4.80 - 4.92 (m, 2 H), 6.87 - 6.92 (m, 1 H), 7.10 - 7.20 (m, 2 H), 8.41 (s, 1 H), 9.53 (t, J=6.5 Hz, 1 H). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min) 2.752 min, m/z 472 (M+H). HPLC (5%-95% 5 CH 3
CN/H
2 0, 40 min) 19.501 min. [a]2 40 C = 0.200 (acetonitrile, 0.09) Example 101 (-N-(4-Fuoro-3 -methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethy1)-tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F -- ,N~ 0 N'N NH - OH1 \/N O N 10 Step 1: Preparation of (-)-((3R*,6S*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 3) 0 OH The third eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (440 mg). 1 H 15 NMR (500 MHz, DMSO-dr,) 6 ppm 1.07 - 1.27 (m, 2 H), 1.50 - 1.62 (m, 1 H), 1.66 - 1.80 (m, 2 H), 3.02 - 3.35 (m, 6 H), 3.89 - 4.00 (m, 1 H), 4.42 (t, J=5.1 Hz, 1 H). SFC (AD-H, 20% ethanol) 3.48 min. LC/MS (5% -95%, CH 3
CN/H
2 0, 12 min.) 4.154 min, m/z 257 (M+H). [a] 22
.
4 C = -1.469 (acetonitrile, 2.37) 20 Step 2: Preparation of -)-N-(4-fluoro-3-methoxvbenzvl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-tetrahydro 2H-pyran-2-vl)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide F 'N.N --- N NH OH O N In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide 25 (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (296 mg, 0.862 mmol) was dissolved in N,N-dimethyl acetamide (3 mL). N,N-Diisopropylethylamine (111 mg, 188 WO 2009/016498 PCT/IB2008/002046 0.862 mmol) was added, and the mixture was stirred at room temperature for 30 min. A solution of (-) ((3R*,6S*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 3) (442 mg, 1.72 mmol) in N,N dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 *C for 14 hours. After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and 5 chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20-50% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold). The first eluting peak (47 min) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (206 mg). 'H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.41 - 1.71 (m, 3 H), 1.71 - 1.85 (m, 1 H), 2.47 - 2.52 (m, 1 H), 2.81 (s, 3 H), 3.34 - 3.43 (m, 1 H), 3.45 - 3.53 (m, 1 H), 3.69 - 3.77 (m, 1 H), 3.81 (s, 3 H), 3.92 10 4.06 (m, 1 H), 4.43 - 4.54 (m, 2 H), 4.77 - 4.97 (m, 2 H), 6.86 - 6.93 (m, 1 H), 7.13 (dd, J=1 1.4, 8.4 Hz, 1 H), 7.17 (dd, J=8.5, 1.8 Hz, 1 H), 8.41 (s, 1 H), 9.52 (t, J=6.4 Hz, 1 H). LC/MS (5%-95%
CH
3
CN/H
2 0, 5 min) 2.753 min m/z 472 (M+H). HPLC (5%-95% CH 3
CN/H
2 0, 40 min) 19.582 min. [a] 22 .4 C = -0. 154 (acetonitrile, 0.39) 15 Example 102 (+)-N-(4-fIuo ro -3 -meth ox ybeanzyl) -6-(2-(((2 S*,5 R*)-5-(h yd roxymethyl) -tetra hyd ro-2H-pyra n-2 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F N N /\ // 0 N Step 1: Preparation of (+)-((3R*,6S*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-vi)methanol (Peak 4) 0 20 -OH The fourth eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (390 mg). 'H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.27 (m, 2 H), 1.50 - 1.62 (m, I H), 1.66 - 1.80 (m, 2 H), 3.02 - 3.35 (m, 6 H), 3.89 - 4.00 (m, 1 H), 4.42 (t, J=5.12 Hz, 1 H). SFC (AD-H, 20% ethanol) 3.402 min. 25 LC/MS (5%-95%, CH 3
CN/H
2 0, 12 min.) 4.153 min, m/z 257 (M+H). (a] 22
.
4 co = 0.194 (acetonitrile, 1.99) 189 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of (+)-N-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) tetrahydro-2H-pVran-2-vl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F 0 - ,N. NO NNN NH - OH O N In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard 5 pressure, N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxam ide, Example 9) (275 mg, 0.801 mmol) was dissolved in N,N-dimethyl acetamide (3 mL). N,N-Diisopropylethylamine (104 mg, 0.801 mmol) was added, and the mixture was stirred at room temperature for 30 min. A solution of (+) 10 ((3R*,6S*)-6-(iodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 4) (410 mg, 1.60 mmol) in N,N dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 *C for 14 hours. After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30-50% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold). The first eluting peak (39 min) was 15 isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (130 mg). 1 H NMR (500 MHz, DMSO-d 6 ) 6 ppm 1.41 - 1.71 (m, 3 H), 1.71 - 1.85 (m, 1 H), 2.47 - 2.52 (m, 1 H), 2.81 (s, 3 H), 3.34 - 3.43 (m, 1 H), 3.45 - 3.53 (m, 1 H), 3.69 - 3.77 (m, 1 H), 3.81 (s, 3 H), 3.92 4.06 (m, 1 H), 4.43 - 4.54 (m, 2 H), 4.77 - 4.97 (m, 2 H), 6.86 - 6.93 (m, 1 H), 7.13 (dd, J=1 1.4, 8.4 Hz, 1 H), 7.17 (dd, J=8.5, 1.8 Hz, 1 H), 8.41 (s, 1 H), 9.52 (t, J=6.4 Hz, 1 H). LC/MS (5%-95% 20 CH 3
CN/H
2 0, 5 min.) 2.751 min, m/z 472 (M+H). HPLC (5%-95% CH 3
CN/H
2 0, 40 min.) 19.586 min. [a]22. CD = 0.267 (acetonitrile, 0.45) Example 103 N-(3-Methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 25 yl)-2-methylpyrimidine-4-carboxamide N O N'N NH 'OH O N 190 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of rac-(3,4-dihydro-2H-pyran-2-vl)methy 4-methylbenzenesulfonate 0 \ -O 0 A mixture of (3,4-dihydro-2H-pyran-2-yl)methanol (10 g, 87.6 mmol), p-toluenesulfonyl chloride (16.7 g, 87.6 mmol), and pyridine (20 mL) was stirred at room temperature overnight. The 5 reaction was cooled in an ice bath and water (50 mL) was added slowly while keeping the mixture cold. The mixture was then extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with 3N hydrochloric acid, dried over magnesium sulfate, and concentrated to afford the title compound as an oil (20.2 g, 86%). Step 2: Preparation of rac-((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl 4 10 methylbenzenesulfonate OH O 0 To a solution of rac-(3,4-dihydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 5.6 mmol) in dry tetrahydrofuran (10 mL) cooled to O *C was added a 1M BH 3 /THF solution (16.8 mL, 16.8 mmol) drop-wise. After complete addition, the reaction was brought to room temperature and stirred 15 overnight. The reaction was treated with 2.5 N NaOH (13.4 mL) by careful drop-wise addition followed by H 2 0 2 (4.6 mL), and then the mixture was heated to 55 *C for 1 h. The mixture was cooled in an ice bath and K 2
CO
3 was added until the aqueous layer was saturated (-7 g). The resulting mixture was stirred for 30 min and then was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product mixture 20 was purified by reverse phase preparative HPLC to afford the title compound as an oil (3.69 g, 97%). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.37 min, m/z 287 (M+H). Step 3: Preparation of N-(3-methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-vl)-2-methylpyrimidine-4-carboxamide N NN ''O NH -N 'TOH O N 25 A mixture of N-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 6 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (400 mg, 1.23 mmol), rac-((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (704 mg, 2.46 mmol), triethylamine (1.37 mL, 9.84 mmol), and dimethylacetamide (2 mL) was stirred at 85 30 *C for 3 days. The reaction mixture was purified by reverse phase preparative HPLC and the peak containing the desired regioisomer was isolated. Further separation by supercritical fluid 191 WO 2009/016498 PCT/IB2008/002046 chromatography (Chiralcel AS-H, 30 x 250 mm, 12% methanol, 70 mL/min) and isolation of the first eluting enantiomer afforded the title compound (40 mg). MS (ES+) m/z 439 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.39 (d, J=10.3 Hz, 1 H), 1.78 - 1.90 (m, 1 H), 1.99 (d, J=8.4 Hz, 1 H), 2.83 (s, 3 H), 2.91 (t, J=10.4 Hz, 1 H), 3.34 - 3.49 (m, 1 H), 3.68 - 3.78 (m, 4 H), 3.80 - 3.93 (m, 2 H), 4.51 (d, J=6.6 5 Hz, 2 H), 4.77 (d, J=4.8 Hz, 1 H), 4.81 - 4.95 (m, 2 H), 6.83 (d, J=8.1 Hz, 1 H), 6.88 - 6.97 (m, 2 H), 7.24 (t, J=8.1 Hz, 1 H), 8.42 (s, 1 H), 9.48 (t, J=6.4 Hz, 1 H). Example 104 N-(3-Methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)-2-methylpyrimidine-4-carboxamide O N N NH - 'OH \/N O N 10 Isolation of the second eluting enantiomer from the product mixture described in Example 103 afforded the title compound (40 mg). MS (ES+) m/z 439 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.25 - 1.52 (m, 2 H), 1.76 - 1.90 (m, 1 H), 1.99 (d, J=11.0 Hz, 1 H), 2.83 (s, 3 H), 2.85 - 2.96 (m, 1 H), 3.36 - 3.49 (m, 1 H), 3.68 - 3.79 (m, 4 H), 3.84 - 3.95 (m, 1 H), 4.52 (d, J=6.6 Hz, 2 H), 4.72 - 4.95 (m, 15 3 H), 6.84 (d, J=1.5 Hz, 1 H), 6.89 - 6.97 (m, 2 H), 7.24 (t, J=8.1 Hz, 1 H), 8.42 (s, 1 H), 9.48 (t, J=6.2 Hz, 1 H). Example 105 (+)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F H N N OH O N 20 A mixture of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 (trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (461 mg, 1.34 mmol), rac-((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl 4 25 methylbenzenesulfonate (prepared as described in step 2 of the synthesis of N-(3-methoxybenzyl)-6 (2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide, Example 103) (500 mg, 1.75 mmol), and triethylamine (1.50 mL, 10.7 mmol) was heated in N,N-dimethylacetamide (15 mL) at 85 *C for 18 hours. The mixture was purified by reverse phase preparative HPLC. The racemate was further separated by supercritical fluid chiral chromatography 192 WO 2009/016498 PCT/IB2008/002046 (Chiralcel AD-H column, 30 x 250 mm, 50% 2-propanol, 70 mL/min) and the first eluting isomer was isolated to afford the title compound (25 mg, 4%). MS (ES+) m/z 458 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.26 - 1.48 (m, 2 H), 1.77 - 1.88 (m, 1 H), 1.91 - 2.03 (m, 1 H), 2.74 - 2.95 (m, 4 H), 3.38 - 3.46 (m, 1 H), 3.64 - 3.75 (m, 1 H), 3.76 - 3.92 (m, 4 H), 4.49 (d, J=6.59 Hz, 2 H), 4.74 - 4.98 5 (m, 3 H), 6.81 - 6.96 (m, 1 H), 7.06 - 7.23 (m, 2 H), 8.40 (s, 1 H), 9.50 - 9.64 (m, 1 H). [a])21 = +9.1* (c = 0.7, dichloromethane) Example 106 (-)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl) 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F \ 0N -, H N N OH O N 10 Isolation of the second eluting isomer by supercritical fluid chiral chromatography (Chiralcel AD-H column, 30 x 250 mm, 50% 2-propanol, 70 mL/min) of the racemic mixture provided in Example 105 afforded the title compound (21 mg, 3%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.27 - 1.48 (m, 2 H), 1.78 - 1.89 (m, 1 H), 1.92 - 2.03 (m, 1 H), 2.77 - 2.93 (m, 4 H), 3.38 - 3.48 (m, 1 H), 3.67 - 3.75 (m, 15 1 H), 3.77 - 3.93 (m, 4 H), 4.49 (d, J=6.59 Hz, 2 H), 4.74 - 4.96 (m, 3 H), 6.83 - 6.95 (m, 1 H), 7.08 7.23 (m, 2 H), 8.40 (s, 1 H), 9.50 - 9.64 (m, 1 H). Example 107 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F --- N O N -N O H N -OH O N. 20 Step 1: Preparation of (5-oxo-tetrah ydro-2 H-pyra n-2-yl)m ethyl 4-methylbenzenesulfonate NH O 0 A solution of dichloromethane (40 mL) and dimethylsulfoxide (1.37 mL, 19.3 mmol) was cooled to -78 *C and oxalyl chloride (0.84 mL, 9.64 mmol) was added drop-wise. rac-((2R*,5S*)-5 25 hydroxy-tetrahydro-2H-pyran-2-yl)methy 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of rac-N-(3-Methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro-2H-pyran-2 193 WO 2009/016498 PCT/IB2008/002046 yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 103) (2.51 g, 8.77 mmol) in dichloromethane (20 mL) was then added via pipette. The mixture was stirred at -78 0C for 15 min and then triethylamine (6.11 mL, 43.8 mmol) was added drop-wise. After 5 min, the dry ice bath was removed and the mixture allowed to warm to room temperature over 30 minutes. The mixture was 5 washed with sat. NaHCO 3 (2 x 20 mL), brine (2 x 20 mL), and water (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was purified by reverse phase preparative HPLC to afford the title compound as an oil. (2.43 g, 97%). MS (ES+) m/z 285 (M+H). Step 2: Preparation of 1,5-dioxaspiro[2.5loct-6-ylmethy 4-methylbenzenesulfonate S-0 0 10 0 5-Oxo-tetrahydro-2H-pyran-2-yl)methy 4-methylbenzenesulfonate (2.4 g, 8.4 mmol) in dimethylsulfoxide (25 mL) was added to a dry mixture of trimethylsulfoxonium iodide (3.72 g, 16.9 mmol) and potassium t-butoxide (1.89 g, 16.9 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solution was poured into water (200 mL) and stirred for 30 min. Ethyl 15 acetate and brine were added and the mixture extracted with ethyl acetate (3 x 20 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated to afford the title compound as an oil (1.32 g). LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95% CH 3 CN, 1 min.): 2.72 min, m/z 321 (M+Na). Step 3: Preparation of (5-hydroxy-5-(hydroxymethyl)-tetrahvdro-2H-pyran-2-yl)methyl 4 20 methylbenzenesulfonate 0 OOH O OH 0 1,5-dioxaspiro[2.5]oct-6-ylmethy 4-methylbenzenesulfonate (1.3 g, 4.4 mmol) was taken up in tetrahydrofuran (6 mL) and water (3 mL). The resulting solution was treated with perchloric acid (1 mL) and the reaction stirred at room temperature for 3 hours. The product mixture was purified by reverse 25 phase preparative HPLC to afford the title compound. LC/MS (5%-95% CH 3
CN/H
2 0, 4 min.; 95%
CH
3 CN, 1 min.): 2.23 min, m/z 317 (M+H). 194 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of rac-N-(4-fluoro-3-methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-5 (hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F - N / o N OH NH N OH 0 N A mixture of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4 5 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 (trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (116 mg, 0.337 mmol), (5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methy 4 methylbenzenesulfonate (160 mg, 0.506 mmol), triethylamine (0.38 mL, 2.70 mmol), and dimethylacetamide (1 mL) was stirred at 85 *C overnight. The reaction mixture was purified by reverse 10 phase preparative HPLC to provide a mixture of isomers which was further separated by supercritical fluid chromatography (Pegasus, 30 x 250 mm, 20% n-butanol, 70 mL/min) / (Diol, 30 x 250 mm, 25% n-butanol, 70 mL/min) to afford the title compound (20 mg, 12%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min) 2.545 min, m/z 488 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) J ppm 1.40 - 1.50 (m, 2 H), 1.74 (d, J=9.2 Hz, 1 H), 1.84 - 1.98 (m, 1 H), 2.83 (s, 3 H), 2.97 (d, J=1 1.0 Hz, I H), 3.33 - 3.38 (m, 1 H), 3.40 15 - 3.46 (m, 1 H), 3.56 (d, J=11.0 Hz, 1 H), 3.82 (s, 3 H), 3.93 (d, J=5.9 Hz, 1 H), 4.51 (d, J=6.2 Hz, 3 H), 4.89 (d, J=5.5 Hz, 2 H), 6.87 - 6.94 (m, 1 H), 7.15 (td, J=12.2, 8.2 Hz, 2 H), 8.14 (s, 1 H), 8.42 (s, 1 H), 9.50 (t, J=6.4 Hz, 1 H). Example 108 rac-N-(4-FIuoro-3-methoxybenzyl)-6-(2-(((2R*,5R*)-5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H 20 pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide F
-
N,N.. 0 NN O0 NOH O N Isolation of a second eluting isomer from the product mixture described in Example 107 afforded the title compound (30 mg, 18%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min) 2.531 min, m/z 488 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.24 (br. s., 1 H), 1.44 - 1.84 (m, 6 H), 2.83 (s, 3 H), 3.14 25 (d, J=1.8 Hz, 2 H), 3.41 - 3.53 (m, 1 H), 3.84 (s, 3 H), 3.85 - 3.94 (m, 1 H), 4.51 (d, J=6.2 Hz, 2 H), 4.82 - 4.93 (m, 2 H), 6.84 - 6.95 (m, 1 H), 7.15 (td, J=12.0, 8.2 Hz, 2 H), 8.42 (s, 1 H), 9.50 (t, J=6.2 Hz, 1 H). 195 WO 2009/016498 PCT/IB2008/002046 Example 109 rac-N-(3-Methoxybenzyl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,4 triazol-3-yl)-2-methylpyrimidine-4-carboxamide - N O -O / NZ O N N OH N N- I Or 5 Step 1: Preparation of dimethyl 2-methylpyrimidine-4,6-dicarboxylate 0 0 N -,N 4,6-Dichloro-2-methylpyrimidine (24 g, 147 mmol), Pd(Ph 3
P)
2 Cl 2 (1.03 g, 1.47 mmol), triethylamine (45.1 mL, 324 mmol), and methanol (400 mL) were added to a 1 L high-pressure vessel. The vessel was pressurized to 500 psi with carbon monoxide and heated to 100 *C for 10 h. The 10 mixture was filtered and the filtrate concentrated. The residue was suspended in a mixture of ethyl acetate/tetrahydrofuran (2/1) and the mixture was refluxed for 30 min. After cooling to below 40 *C, the mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with ethyl acetate. Fractions containing product were concentrated. The residue was slurried in a mixture of acetone/hexanes (2/1), filtered and dried in vacuo at 45 *C to 15 afford the title compound as a light yellow solid. Step 2: Preparation of N-(3-methoxybenzyl)-2-methylpyrimidine-4,6-dicarboxamide 0 0 O N N Dimethyl 2-methylpyrimidine-4,6-dicarboxylate (5.0 g, 23.8 mmol), 3-methoxybenzylamine (3.59 g, 26.2 mmol), and 2-methyltetrahydrofuran (31.7 mL) were combined in an 50 mL microwave 20 reaction tube and heated to 90 *C for 15 min. The reaction mixture was filtered through a plug of silica gel, and the filtrate was concentrated. The residue was suspended in methanol (25 mL) and a solution of ammonia in methanol (7 N, 3.0 mL) was added. The mixture was stirred at room temperature overnight and then concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/heptane/methanol, 65/34/1) to afford the title compound as a white solid (2.2 g). MS (ES+) m/z 25 301 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) d ppm 9.46 (t, J=6.3 Hz, 1 H), 8.27 (br. s., 1 H), 8.22 (s, 1 H), 7.98 (br. s., 1 H), 7.20 (t, J=8.1 Hz, 1 H), 6.85 - 6.90 (m, 2 H), 6.79 (dd, J=8.3, 2.1 Hz, 1 H), 4.45 (d, J=6.2 Hz, 2 H), 3.70 (s, 3 H), 2.77 (s, 3 H). 196 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-methoxvbenzyl)-2-methyl-6-(1H-1,2,4-triazol-3-vl)pvrimidine-4 carboxamide 0 N N H -O N N' N-(3-Methoxybenzyl)-2-methylpyrimidine-4,6-dicarboxamide (1.49 g, 4.96 mmol) was treated 5 with dimethylformamide dimethylacetal (50 mL, 380 mmol) followed by heating at 101 *C for 2h. A short path distillation was utilized to collect the generated methanol. The solvent was then removed in vacuo to afford a crude residue. The residue was dissolved in glacial acetic acid (20 ml ) and treated with monohydrazine hydrate (0.75 mL, 14.9 mmol). The mixture was heated at 90 *C for 2 hours and then allowed to cool to room temperature. The mixture was poured into H 2 0 (75 mL) and left to stand 10 at room temperature overnight. The resulting solids were filtered and dried to afford the title compound (1.11 g, 69 %). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.95 min, m/z 325 (M+H). Step 4: Preparation of rac-N-(3-methoxvbenzyl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2 y)methyl)-1 H- 1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide. - N O -O N O N \ OH N N'N\"O 15 N-(3-Methoxybenzyl)-2-methyl-6-(IH-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide (0.070 g, 0.22 mmol) was treated with rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3 methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)- 1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 61) (0.085 g, 0.28 mmol) and 1,8 20 diazabicyclo[5.4.0]undec-7-ene (0.082 g, 0.54 mmol) in acetonitrile (5 mL). After the reaction was stirred for 12 h at 75 *C, the mixture was concentrated to a crude residue that was purified via reverse phase chromatography (40-60% acetonitrile/water, 55 min) to afford the title compound as a white solid (30 mg, 31%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 3.83 min, m/z 455 (M+H). 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.78 (3 H, s), 3.30 - 3.38 (4 H, m), 3.42 (1 H, d, J=5.9 Hz), 3.74 (3 H, s), 3.79 25 (1 H, br. s.), 3.90 (2 H, d, J=9.2 Hz), 4.29 - 4.36 (1 H, m), 4.38 - 4.46 (1 H, m), 4.50 (2 H, d, J=6.2 Hz), 4.60 - 4.69 (1 H, m), 6.82 (1 H, d, J=7.7 Hz), 6.93 (2 H, br. s.), 7.24 (1 H, t, J=8.1 Hz), 8.36 (1 H, s), 8.69 (1 H, s), 9.39 (1 H, t, J=6.2 Hz). Example 110 N-(3-Methoxybenzyl)-6-(1 -((trans-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-2 30 methylpyrimidine-4-carboxamide 197 WO 2009/016498 PCT/IB2008/002046 HN -N NNN Step 1: Preparation of (trans-4-((ter-butoxycarbonyl)amno)cyclohexyl)methyl 4-nitrobenzenesulfonate
NO
2 Is O NOO The commercially available tert-butyl (trans)-4-(hydroxymethyl)cyclohexylcarbamate (0.30 g, 5 1.3 mmol) was taken up in dichloromethane (7 mL) and treated with pyridine (0.16 mL, 2.0 mmol) before dripping in a solution of 4-nitrobenzene-1-sulfonyl chloride (0.43 g, 1.96 mmol) in dichloromethane (3.0 mL). The reaction was allowed to stir at room temperature for 15 h. The mixture was washed with water (5 mL), 5% aqueous hydrochloric acid (3 mL), followed by water ( 5 mL) before drying over sodium sulfate. The organic layer was concentrated to a crude oily residue that crystallized 10 to afford the title compound as a beige solid (0.44 g, 81%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 5.48 min, m/z 439 (M+Na). Step 2: Preparation of tert-butvl (trans)-4-((3-(6-((3-methoxybenzyl)carbamovl)-2-methylpvrimidin-4-vl) 1 H-1.2,4-triazol-1 -yl)methyl)cyclohexylcarbamate -0 NN - HN N N-N, ' 0 15 (trans-4-((tert-Butoxycarbonyl)amino)cyclohexyl)methy 4-nitrobenzenesulfonate (0.096 g, 0.23 mmol) and N-(3-methoxybenzyl)-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of rac-N-(3-methoxybenzyl)-6-(1-(((2R*,5S*)-5 (hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1H-1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 109) (0.050 g, 0.15 mmol) were treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL, 20 0.15 mmol) in acetonitrile ( 5mL) at 75 *C for 12 h. The mixture was concentrated and the residue was purified via reverse phase chromatography (10-90% acetonitrile/water, 30 min) to afford the title compound as a tan oil (0,057 mg, 69%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min): 3.10 min, m/z 536 (M+H). 198 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-methoxybenzyl)-6-(1-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4-triazol 3-yl)-2-methylpyrimidine-4-carboxamide. HN -O N 1 N \ N N NH2 N NN tert-Butyl (trans)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1H-1,2,4 5 triazol-1-yl)methyl)cyclohexylcarbamate (0.057 g, 0.11 mmol) was taken up in dichloromethane (2 mL) and treated with trifluoroacetic acid (1.0 mL, 7.7 mmol). The reaction was stirred at ambient temperature for 3 h, diluted with dichloromethane (5 mL), and then neutralized with 2.5 N aqueous NaOH to achieve pH 7-8. The organic layer was separated, washed with water (3 mL), dried over sodium sulfate, and concentrated to afford the title compound (0.037 g, 51%). LC/MS (5%-95% 10 CH 3
CN/H
2 0, 6 min): 3.78 min, m/z 436 (M+H). Example 111 N-(3-Methoxybenzyl)-6-(1 -(((trans)-4-acetamidocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide HN0 -O N N N N- N 15 N-(3-Methoxybenzyl)-6-( -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 110) (0.034 g, 0.078 mmol) was taken up in dichloromethane (2 mL) and treated with acetyl chloride (0.006 mL, 0.086 mmol) and triethylamine (0.012 mL, 0.086 mmol). After 1 h, the reaction was concentrated, and the residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 30 minutes) to afford the 20 title compound as a clear oil (11.7 mg, 31%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 4.07 min, m/z 477 m/e. 1 H NMR (400 MHz, DMSO-d6) d ppm 1.09 (4 H, br. s.) 1.22 - 1.33 (1 H, m) 1.60 (2 H, br. s.) 1.73 - 1.84 (2 H, m) 1.75 (3 H, s) 2.78 (3 H, s) 3.46 (1 H, br. s.) 3.74 (3 H, s) 4.16 (2 H, d, J=6.95 Hz) 4.50 (2 H, d, J=6.22 Hz) 6.82 (1 H, d, J=8.05 Hz) 6.92 (2 H, br. s.) 7.24 (1 H, t, J=8.05 Hz) 7.64 (1 H, d, J=7.69 Hz) 8.36 (1 H, s) 8.72 (1 H, s) 9.39 (1 H, t, J=6.04 Hz) 25 Example 112 N-(3-Methoxybenzyl)-2-methyl-6-(1 -(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-1 H-1,2,4 triazol-3-yl)pyrimidine-4-carboxamide 199 WO 2009/016498 PCT/IB2008/002046 - N O -O N H -0 N N/ N\ : .. N-(3-Methoxybenzyl)-6-(1-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 110) (0.050 g, 0.115 mmol) was taken up in dichloromethane (1 mL) and treated with methane sulfonyl chloride (0.009 mL, 0.115 5 mmol) and triethylamine (0.018 mL, 0.126 mmol). After 1 h, the reaction was concentrated to a crude residue. The residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 25 minutes) to afford the title compound as a clear oil (38.1 mg, 64%). LC/MS (5%-95% CH 3
CN/H
2 0, 6 min): 2.57 min, m/z 514 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.00 - 1.26 (5 H, m), 1.58 (2 H, d), 1.79 (1 H, br. s.), 1.88 (2 H, d, J=9.9 Hz), 2.76 (3 H, s), 2.86 (3 H, s), 3.02 (1 H, br. s.), 3.71 (3 H, 10 s), 4.14 (2 H, d, J=7.0 Hz), 4.48 (2 H, d, J=6.2 Hz), 6.80 (1 H, d, J=7.9 Hz), 6.90 (2 H, br. s.), 7.15 7.29 (1 H, m), 8.33 (1 H, s), 8.70 (1 H, s), 9.37 (1 H, br. s.) Example 113 2-((trans)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidi-4-yl)-1 H-1,2,4-triazol-1 yl)methyl)cyclohexylamino)-2-oxoethyl acetate HN N x/ 15 N-(3-Methoxybenzyl)-6-(1 -(((trans)-4-aminocyclohexyl)methyl)- 1 H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 110) (0.085 g, 0.195 mmol) was taken up in dichloromethane (2 mL) and treated with acetoxy acetyl chloride (0.025 mL, 0.234 mmol) and triethylamine (0.041 mL, 0.293 mmol). After stirring 2 hours at room temperature, the reaction was 20 concentrated and the residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 25 minutes) to afford the title compound (0.095 g, 91%). Example 114 N-(3-Methoxybenzyl)-6-(1 -(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3 yl)-2-methylpyrimidine-4-carboxamide HN -0 / \\N N N NNOH 25 2-((trans)-4-((3-(6-((3-Methoxybenzyl)carbam oyl)-2-methylpyrim idin-4-yl)- 1 H- 1,2,4-triazol- 1 yl)methyl)cyclohexylamino)-2-oxoethyl acetate (prepared as described in Example 113) (0.095g, 0.18 200 WO 2009/016498 PCT/IB2008/002046 mmol) was taken up in acetonitrile (3 mL) and stirred with 2.5 N aqueous NaOH (2.0 mL) for 2 hours at room temperature. The acetonitrile was removed in vacuo and the aqueous solution was acidified to pH 5 via 10% aqueous hydrochloric acid to afford a solid. The solid was filtered, washed with water (2 x 3 mL), and dried to afford the title compound as a beige solid (11.1 mg, 11.3%). LC/MS (5%-95% 5 CH 3
CN/H
2 0, 6 min): 3.45 min, m/z 494 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.00 - 1.16 (2 H, m), 1.16 - 1.30 (2 H, m), 1.58 (2 H, d, J=13.2 Hz), 1.73 (2 H, d, J=9.5 Hz), 2.52 (2 H, s), 2.76 (3 H, s), 3.42 - 3.59 (1 H, m), 3.66 - 3.78 (4 H, m), 4.15 (2 H, d, J=6.6 Hz), 4.48 (2 H, d, J=6.2 Hz), 5.30 (1 H, t, J=5.5 Hz), 6.80 (1 H, d, J=10.6 Hz), 6.86 - 6.95 (2 H, m), 7.16 - 7.26 (1 H, m), 7.35 (1 H, d, J=8.4 Hz), 8.34 (1 H, s), 8.71 (1 H, s), 9.29 - 9.40 (1 H, m). 10 Example 115 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 1 H-1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide F 0 -O N O N OH Step 1: Preparation of methyl 6-((4-fluoro-3-methoxvbenzvl)carbamoyl)-2-methylpyrimidine-4 15 carboxylate 0 0 N O F H Dimethyl 2-methylpyrimidine-4,6-dicarboxylate (prepared as described in step 1 of the synthesis of rac-N-(3-Methoxybenzyl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1H 1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 109) (4.50 g, 21.4 mmol), 4-fluoro-3 20 methoxybenzylamine (prepared as described in step 3 of the synthesis of N-(4-fluoro-3 methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (3.65 g, 23.6 mmol), and 2-methyltetrahydrofuran (21.4 mL) were combined in an 80 mL microwave reaction tube and heated to 110 *C for 30 min. The reaction mixture was filtered through a plug of silica gel eluting with 65/35, ethyl acetate/heptane. The filtrate was concentrated and purified 25 by silica gel chromatography (heptane/acetone, 4/1) to afford the title compound as a white solid (1.95 g). MS (ES+) m/z 334 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 9.53 (t, J=6.3 Hz, 1 H), 8.20 (s, 1 H), 7.14 (dd, J=7.8, 1.9 Hz, 1 H), 7.07 - 7.13 (m, J=11.5, 8.2 Hz, 1 H), 6.85 (ddd, J=8.3, 4.4, 1.9 Hz, 1 H), 4.45 (d, J=6.4 Hz, 2 H), 3.91 (s, 3 H), 3.78 (s, 3 H), 2.77 (s, 3 H). 201 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-4-(4-fluoro-3-methoxvbenzyl)-2-methylpyrimidine-4,6-dicarboxamide 0 0 N
NH
2 Methyl 6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidine-4-carboxylate (1.945 g, 5.84 mmol) was dissolved in a mixture of methanol (80 mL) and dichloromethane (15 mL). A solution 5 of ammonia in methanol (7 N, 16.7 mL, 117 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was concentrated to minimal volume. The resulting precipitate was filtered and washed with ethyl ether to afford the title compound as a white solid (1.785 g). MS (ES+) m/z 319 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 9.48 (t, J=6.4 Hz, 1 H), 8.27 (s, 1 H), 8.22 (s, 1 H), 7.98 (s, 1 H), 7.14 (dd, J=7.9, 1.7 Hz, 1 H), 7.11 (dd, J=11.5, 8.3 Hz, 1 H), 6.86 (ddd, J=8.2, 4.4, 1.9 Hz, 1 10 H), 4.45 (d, J=6.3 Hz, 2 H), 3.78 (s, 3 H), 2.77 (s, 3 H). Step 3: Preparation of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(1H-1,2,4-triazol-3-vl)pyrimidine-4 carboxamide. 0 F N NN - N -O N WNH N-4-(4-Fluoro-3-methoxybenzyl)-2-methylpyrimidine-4,6-dicarboxamide (1.0 g, 3.1 mmol) was 15 dissolved in dimethylformamide dimethylacetal (25 mL), and the reaction was refluxed for approximately 2 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in acetic acid (20 mL). Hydrazine hydrate (1.0 mL) was added and the reaction mixture was heated at 90 *C for 1 h. The reaction mixture was poured into water and left to sit overnight. The resulting precipitate was collected by suction filtration and washed with water and diethyl ether to 20 afford the title compound (702 mg, 65%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 4.60 min, m/z 343 (M+H). Step 4: Preparation of rac-N-(4-fluoro-3-methoxvbenzvl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1,4 dioxan-2-vl)methyl)-1 H-1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide F 0 -O N Oa N X OH N N' ( 25 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide (110 mg, 0.321 mmol) and rac-((2R*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3 methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 61) (126 mg, 0.418 mmol) were stirred in acetonitrile (5 202 WO 2009/016498 PCT/IB2008/002046 mL), and 1,8-diazobicyclo[5.4.0]undec-7ene (73.4 mg, 0.482 mmol) was subsequently added. The reaction was heated at 75 0C overnight before cooling to room temperature and concentrating under reduced pressure. The residue was dissolved in acetonitrile (2 mL)/water (1 mL) and was purified by reverse phase HPLC (20-minute hold at 20% B followed by a 30 minute gradient from 20% B to 80% 5 B (A = 0.1% TFA / water and B = 0.1% TFA / acetonitrile)). The combined fractions were lyophilized to afford the title compound (4.5 mg, 2.4%) as the TFA salt. LC/MS: (5%-95% CH 3
CN/H
2 0, 8 min.; 95%
CH
3 CN, 2 min.) 4.73 min, m/z 473 (M+H). 1 H NMR (400 MHz, DMSO-de) 6 ppm 9.48 (t, 1 H), 8.71 (s, 1 H), 8.33 (s, 1 H), 7.04 - 7.23 (m, 2 H), 6.87 (s, 1 H) 4.19 - 4.53 (m, 5 H), 3.56 - 4.05 (m, 6 H), 3.78 (s, 3 H), 3.19 - 3.49 (m, 2 H), 2.75 (s, 3 H). 10 Example 116 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -((trans-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide F N -0X N xN N 2 N N - o= N N - N H Step 1: Preparation of tert-butyl trans-4-((3-(6-((4-fluoro-3-methoxybenzvl)carbamoyl)-2 15 methylpyrimidin-4-vl)-1 H- 1,2,4-triazol-1 -vl)methyl)cyclohexylcarbamate F N 0 F-P HN0 -O N H N 'II, " ' "(:: N
N
N-(4-FIuoro-3-methoxybenzyl)-2-methyl-6-( 1 H- 1,2,4-triazol-3-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of rac-N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2R*,5S*) 5-(hydroxymethyl)- 1,4-dioxan-2-yl)methyl)- 1 H- 1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide, 20 Example 115) (702 mg, 2.05 mmol) and (trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl 4 methylbenzenesulfonate (prepared as described in step 7 of the synthesis of N-(3-methoxybenzyl)-6 (2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (786 mg, 2.05 mmol) were stirred in acetonitrile (40 mL), and 1,8-diazobicyclo[5.4.0]undec-7ene (480 mg, 3.15 mmol) was subsequently added. The reaction was heated at 75 *C overnight before 25 cooling to room temperature and concentrating under reduced pressure. The residue was purified by reverse phase HPLC using a 40% B to 60% B, 30 minutes (A = 0.1% TFA / water and B = 0.1% TFA / acetonitrile) to afford the title compound (230 mg, 20%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95%
CH
3 CN, 2 min.): 6.28 min, m/z 554 (M+H). 203 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-methoxvbenzvl)-6-(1-((trans-4-aminocyclohexvl)methyl)-1H-1,2,4 triazol-3-yl)-2-methylpyrimidine-4-carboxamide F N IN
HN
-O N~ N
NH
2 N tert-Butyl trans-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)- 1 H 5 1,2,4-triazol-1-yl)methyl)cyclohexylcarbamate (230 mg, 0.415 mmol) was dissolved in 1:1 TFA / dichloromethane (2 mL each), and the reaction was stirred at room temperature for an hour. The reaction was then concentrated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8, and the product was extracted into ethyl acetate. The organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and 10 evaporation of the solvent under reduced pressure afforded the title compound (120 mg, 64% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 4.28 min, m/z 454 (M+H). Example 117 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 -((trans-4-(methylsulfonamido)cyclohexyl)methyl) 1 H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide F - HN 0 0 N H// NFN O 15 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -((trans-4-aminocyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 116) (60 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (26.8 mg, 0.265 mmol) and methanesulfonyl chloride (18.2 mg, 0.159 mmol) were subsequently added, and the reaction was continued overnight 20 at room temperature. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an off-white solid (60 mg, 85% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 5.19 min, m/z 532 (M+H). IH NMR 25 (400 MHz, DMSO-d 6 ) 6 ppm 9.38 (t, 1 H), 8.69 (s, 1 H), 8.31 (s, 1 H), 7.03 - 7.20 (m, 2 H), 6.83 - 7.00 (m, 2 H), 4.40 - 4.52 (m, 2 H), 4.09 - 4.23 (m, 2 H), 3.80 (s, 3 H), 2.94 - 3.12 (m, 1 H), 2.86 (s, 3 H), 2.75 (s, 3 H), 1.68 - 1.99 (m, 3 H), 1.50 - 1.66 (m, 2 H), 0.90 - 1.29 (m, 4 H). Example 118 N-(4-fluoro-3-methoxybenzyl)-6-(1-((trans-4-acetamidocyclohexyl)methyl)-1H-1,2,4-triazol-3-yI) 30 2-methylpyrimidine-4-carboxamide 204 WO 2009/016498 PCT/IB2008/002046 F 0 F- HN 0 -O N H N N N N O N-(4-Fluoro-3-methoxybenzyl)-6-(1 -((trans-4-aminocyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 116) (60 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (26.8 mg, 0.265 mmol) and acetyl chloride (12.5 5 mg, 0.159 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded a crude solid which was dissolved in acetonitrile (1 mL), 10 water (0.5 mL), and DMF (0.5 mL) and purified by reverse phase HPLC using a 30 - 60% B, 30 minutes (A = 0.1% TFA / water and B = 0.1% TFA / acetonitrile). The product-containing fractions were combined and concentrated under reduced pressure to afford the title compound as a white solid (14 mg, 17% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 5.16 min, 496 (M+H). H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.37 (t, 1 H), 8.66 (s, 1 H), 8.33 (s, 1 H), 7.54 - 7.68 (m, 1 H), 15 7.04 - 7.22 (m, 2 H), 6.76 - 6.97 (m, 1 H), 4.41 - 4.53 (m, 2 H), 4.04 - 4.18 (m, 2 H), 3.78 (s, 3 H), 3.38 - 3.53 (m, 1 H), 2.76 (s, 3 H), 1.73 - 1.89 (m, 3 H), 1.73 (s, 3 H), 1.40 - 1.63 (m, 2 H), 0.95 1.17 (m, 4 H). Example 119 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -((trans-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,4 20 triazol-3-yl)-2-methylpyrimidine-4-carboxamide F 0 -O N IH N N ' N [ OH N N-N "0O Step 1: Preparation of 2-(trans-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrim idin-4 yl)-1H-1,2,4-triazol-1-yl)methyl)cyclohexylamino)-2-oxoethyl acetate F 0 F- HN 0 -O N H 0 N NN 0\" O 25 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -((trans-4-aminocyclohexyl)methyl)- 1 H-1,2,4-triazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 116) (60 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (26.8 mg, 0.265 mmol) and acetoxyacetyl chloride 205 WO 2009/016498 PCT/IB2008/002046 (21.7 mg, 0.159 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of 5 the solvent under reduced pressure afforded the title compound (56 mg, 76%). LC/MS (5%-95%
CH
3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 5.26 min, m/z 554 (M+H). Step 2: Preparation of N-(4-fluoro-3-methoxybenzvl)-6-(1-((trans-4-(2 h ydroxvyacetamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3-vl)-2-methylpyrimidine-4-carboxamide F N H -O N N N N DOH N N - N 0 10 2-(trans-4-((3-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1H-1,2,4 triazol-1-yl)methyl)cyclohexylamino)-2-oxoethyl acetate (56 mg, 0.10 mmol) was dissolved in acetonitrile (3 mL), and 2.5 N NaOH (1.5 mL) was added. The reaction was continued overnight at room temperature. The pH was adjusted with concentrated hydrochloric acid, and the product was extracted into ethyl acetate (2x). The organic layer was washed with water and saturated sodium 15 chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a solid (26 mg, 50% yield). LC/MS (5%-95%
CH
3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 4.82 min, m/z 512 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.36 (t, 1 H), 8.72 (s, 1 H), 8.31 (s, 1 H), 7.29 - 7.41 (m, 1 H), 6.97 - 7.25 (m, 2 H), 6.79 - 7.00 (m, 1 H), 5.21 - 5.40 (m, 1 H), 4.40 - 4.55 (m, 2 H), 4.06 - 4.23 (m, 2 H), 3.80 (s, 3 H), 3.65 - 3.75 (m, 20 2 H), 3.40 - 3.60 (m, 1 H), 2.77 (s, 3 H), 1.66 - 1.85 (m, 3 H), 1.52 - 1.63 (m, 2 H), 0.99 - 1.31 (m, 4 H). Example 120 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(1 -((trans-4 (methylsulfonamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide F N H 0 N/\// HO O N r O 25 206 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobelZ )-6-cyano-2 methylpyrimidine-4-carboxamide 0 OO Si' 04 CN N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyrimidine-4-carboxamide(prepared 5 as described in step 1 of the synthesis of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans-4 cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 27) (2.2 g, 6.7 mmol) and imidazole (453 mg, 6.7 mmol) were dissolved in dry DMF (36 mL). After cooling to 0 *C, tert-butyldiphenylsilyl chloride (2.2 g, 8.0 mmol) was added. The reaction was permitted to warm to room temperature with stirring for 2 days. The reaction was then diluted with ethyl acetate and washed 10 with water (3x) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (3 g, 79%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 8.48 min, 591 (M+Na). Step 2: Preparation of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-2-methylpyrimidine 4,6-dicarboxamide. 0 0 S' NH 2 0 N4 15 T To a solution of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-6-cyano-2 methylpyrimidine-4-carboxamide (3 g, 5 mmol) in acetone (21 mL) was added 2.5 N sodium hydroxide (11 mL) followed by 30% hydrogen peroxide (3.15 mL). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 20 water and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (2.95 g, 100%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 8.00 min, m/z 609 (M+Na). 207 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-2-methyl-6-(1H-1,2,4 triazol-3-yl)pyrimidine-4-carboxamide. O N Si'O, ): N NNH N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-2-methylpyrimidine-4,6 5 dicarboxamide (2.95 g, 5.0 mmol) was dissolved in dimethylformamide dimethylacetal (45 mL), and the mixture was refluxed for approximately 2 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL). Hydrazine hydrate (1.5 mL) was then added and the mixture was heated at 90 *C for 1 h. After cooling to room temperature, the reaction was poured into water. The pH was adjusted to 7, and the product was extracted into ethyl acetate. 10 The organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound (1.7 g). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 7.88 min, m/z 611 (M+H). Step 4: Preparation of tert-butyl trans-4-((3-(6-((3-(2-(te-butyldiPhenylsiVloxy)ethoxy)-4 15 fluorobenzyl)carbamovl)-2-methylpvrimidin-4-vi)-1 H-1.2,4-triazol-1 -vl)methyl)cyclohexylcarbamate F Si-O O N N NH H O N 0 N N-(3-(2-(tert-Butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-2-methyl-6-(1 H-1,2,4-triazol-3 yl)pyrimidine-4-carboxamide (1.73 g, 2.83 mmol) and (trans-4-((tert butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 7 20 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (1.19 g, 3.12 mmol) were stirred in acetonitrile (50 mL), and 1,8-diazobicyclo[5.4.0]undec-7ene (647 mg, 4.25 mmol) was subsequently added. The reaction was heated at 75 0C overnight before cooling to room temperature and concentrating under reduced pressure. The residue was purified by reverse phase HPLC using a 40% B to 60% B, 30 minutes (A 25 0.1% TFA / water and B = 0.1% TFA / acetonitrile) to afford the title compound (300 mg, 13%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 9.04 min, 822 (M+H). 208 WO 2009/016498 PCT/IB2008/002046 Step 5: Preparation of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzvl)-6-(1-((trans-4 aminocyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide F Si-O 0 - N/ N NH N NH 2 0 N tert-Butyl trans-4-((3-(6-((3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)carbamoyl)-2 5 methylpyrimidin-4-yl)-1H-1,2,4-triazol-1-yl)methyl)cyclohexylcarbamate (300 mg, 0.365 mmol) was dissolved in 1:1 TFA / dichloromethane (3 mL each), and the reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8, and the product was extracted into ethyl acetate. The organic layer was washed with water followed by saturated sodium chloride and concentrated to afford title 10 compound (60 mg, 23%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 7.07 min, 722 (M+H). Steg 6: Preparation of N-(3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-4-fluorobenzl)-2-methyl-6-( -((trans 4-(methylsulfonamido)cyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide F Si-O O N N0 NH N 0 N 15 N-(3-(2-(tert-Butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-6-(1 -((trans-4 aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide (60 mg, 0.0.83 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (16.8 mg, 0.166 mmol) and methanesulfonyl chloride (11.4 mg, 0.0997 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, 20 and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a solid (60 mg, 90%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 7.97 min, 800 (M+H). 209 WO 2009/016498 PCT/IB2008/002046 Step 7: Preparation of N-(4-fluoro-3-(2-hydroxyethoxy)benzvl)-2-methvl-6-(1-((trans-4 (methylsulfonamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)pyrimidine-4-carboxamide F HO O N N N N O N N-(3-(2-(tert-Butyldiphenylsilyloxy)ethoxy)-4-fluorobenzyl)-2-methyl-6-(1 -((trans-4 5 (methylsulfonamido)cyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)pyrimidine-4-carboxamide (60 mg, .075 mmol) was dissolved in THF (2 mL). Tetrabutylammonium fluoride in THF (1 M) (19.6 mg, 0.075 mmol) was subsequently added and the mixture stirred for a couple of hours. The reaction mixture was purified by reverse phase chromatography using an acetonitrile gradient in water (10% - 85% over 30 minutes). The product-containing fractions were combined and neutralized with 2.5 N sodium 10 hydroxide. The product was extracted into ethyl acetate, and the organic layer was washed with saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure. The residue was redissolved in ethyl acetate and washed with saturated ammonium chloride and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound 15 as a solid (5 mg, 10%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 4.57 min, 562 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.40 (t, 1 H), 8.70 (s, 1 H), 8.33 (s, 1 H), 7.58 - 7.76 (m,1 H), 7.05 - 7.23 (m, 2 H), 6.83 - 6.98 (m, 1 H), 4.82 (t, 1 H), 4.41 - 4.53 (m, 2 H), 4.08 - 4.21 (m, 2 H), 3.98 - 4.08 (m, 2 H), 3.61 - 3.78 (m, 2 H), 3.02 - 3.12 (m, 1 H), 2.87 (s, 3 H), 2.76 (s, 3 H), 1.77 - 1.92 (m, 3 H), 1.51 - 1.65 (m, 2 H), 0.98 - 1.33 (m, 4 H). 20 Example 121 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(1 -((trans-4-acetamidocyclohexyl)methyl)-1 H-1,2,4 triazol-3-yl)-2-methylpyrimidine-4-carboxamide F HO 0 N N NH N N H 0 N 210 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of N-(4-fluoro-3-(2-hydroxyethoxv)benzyl)-6-(carbamimidoyl)-2-methylpyrimidine 4-carboxamide F --- ,NH 2 HO 0 HN NH NH O N N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyrimidine-4-carboxamide (prepared 5 as described in step 1 of the synthesis of N-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans-4 cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 27) (700 mg, 2.12 mmol) was dissolved in absolute ethanol (20 mL). Hydrazine hydrate (2.33 g, 46.6 mmol) was added, and the reaction was refluxed for 3 h. The reaction mixture was allowed to cool to room temperature. The reaction was diluted with ethyl acetate and washed with water (3X) and saturated 10 sodium chloride (1X) before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (300 mg, 39%). LC/MS (5%-95%
CH
3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 3.19 min., m/z 363 (M+H). Step 2: Preparation of N-(4-fluoro-3-(2-hydroxvethoxv)benzvl)-2-methyl-6-(1H-1.2,4-triazol-3 VI)pyrimidine-4-carboxamide F HO 0 N NH - N NH /N O N 15 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(carbamimidoyl)-2-methylpyrimidine-4-carboxamide (300 mg, 0.83 mmol) was dissolved in formic acid (3 mL), and the reaction was refluxed overnight. The reaction was then cooled and concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated, and the organic 20 layer was washed with saturated sodium bicarbonate and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (80 mg, 26%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95%
CH
3 CN, 2 min.): 4.77 min, m/z 373 (M+H). Step 3: Preparation of (trans-4-aminocyclohexyl)methyl 4-methylbenzenesulfonate 0 /"
NH
2 S-0 25 O (trans-4-((tert-Butoxycarbonyl)amino)cyclohexyl)methy 4-methylbenzenesulfonate (prepared as described in step 7 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 5) (1.0 g, 2.6 211 WO 2009/016498 PCT/IB2008/002046 mmol) was dissolved in 1:1 TFA / dichloromethane (5 mL each), and the reaction was stirred at room temperature for an hour. The reaction was then concentrated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8, and the product was extracted into ethyl acetate. The organic layer was washed with water followed by saturated sodium chloride, dried over anhydrous 5 sodium sulfate, filtration and concentrated to afforded the title compound (450 mg, 61% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 3.99 min., m/z 284 (M+H). Step 4: Preparation of (trans-4-acetamidocyclohexvl)methyl 4-methylbenzenesulfonate O / NH o 0 (trans-4-Aminocyclohexyl)methyl 4-methylbenzenesulfonate (450 mg, 1.59 mmol) was 10 dissolved in dichloromethane (10 mL). Triethylamine (321 mg, 3.18 mmol) and acetyl chloride (150 mg, 1.91 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride solution before drying over anhydrous sodium sulfate. Filtration and 15 evaporation of the solvent under reduced pressure afforded the title compound as an oil (450 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 5.23 min, m/z 326 (M+H). Step 5: Preparation of N-(4-fluoro-3-(2-hydroxvethoxy)benzyl)-6-(1-((trans-4 acetamidocyclohexyl)methyl)-1 H-1,2,4-triazol-3-vl)-2-methylpyrimidine-4-carboxamide F HO 0 N N NH - \ /N H O N 20 N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(1 H-1,2,4-triazol-3-yl)pyrimidine-4 carboxamide (80 mg, 0.21 mmol) and ((trans-4-acetamidocyclohexyl)methy 4 methylbenzenesulfonate (76.9 mg, 0.236 mmol) were stirred in acetonitrile (5 mL), and 1,8 diazobicyclo[5.4.0]undec-7ene (DBU) (49.1 mg, 0.322 mmol) was subsequently added. The reaction was heated at 75 0C overnight before cooling to room temperature and diluting with ethyl acetate. The 25 organic layer was washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded an oil which was purified by reverse phase HPLC using a 20% B to 60% B, 40 minutes (A = 0.1% TFA / water and B = 0.1% TFA / acetonitrile). The product-containing fractions were combined, and the pH was made basic with 2.5 N sodium hydroxide. The product was extracted into ethyl acetate, and the 30 combined organic layer was washed with saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound (3.9 mg, 3.5%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 4.56 min, m/z 212 WO 2009/016498 PCT/IB2008/002046 326 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.39 (t, 1 H), 8.73 (s, 1 H), 8.32 (s, 1 H), 7.54 - 7.72 (m,1 H), 7.04 - 7.26 (m, 2 H), 6.84 - 6.96 (m, 1 H), 4.80 (t, 1 H), 4.41 - 4.54 (m, 2 H), 4.11 - 4.22 (m, 2 H), 3.96 - 4.09 (m, 2 H), 3.63 - 3.80 (m, 2 H), 3.33 - 3.52 (m, 1 H), 2.76 (s, 3 H), 1.78 - 2.05 (m, 3 H), 1.71 (s, 3 H), 1.48 - 1.65 (m, 2 H), 1.09 - 1.34 (m, 4 H). 5 Example 122 N-(4-Fluoro-3-methoxybenzyl)-6-(5-((trans-4-aminocyclohexyl)methyl)-1,2,4-oxadiazol-3-yl)-2 methylpyrimidine-4-carboxamide F -Q \ -~ HN -F N N'O NH 2 N 0 2 N N : Step 1: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-cyano-2-methylpyrimidine-4-carboxamide 0 S N ON I H F ) 1:1N .:N 10 A mixture of methyl 6-cyano-2-methylpyrimidine-4-carboxylate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide, Example 5) (10.0 g, 56.4 mmol), 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 15 ((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (13.5 g, 70.6 mmol), N,N-diisopropylethylamine (39.3 mL, 226 mmol), and methanol (56.4 mL) was heated to 35 0C for 1 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (500 mL) and 1 N hydrochloric acid (500 mL). The aqueous layer was extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (2 x 20 250 mL) followed by brine, dried over sodium sulfate, and concentrated.. The crude product was purified by silica gel chromatography (2/1, heptane/ethyl acetate) to afford the title compound as a white solid (11.7 g). MS (ES+) m/z 301 (M+H). Step 2: Preparation of N-(4-fluoro-3-methoxvbenzyl)-6-(carbamimidoyl)-2-methylpyrimidine-4 carboxamide F 0 - HN -0 N-OH N N NH 2 25 N-(4-Fluoro-3-methoxybenzyl)-6-cyano-2-methylpyrimidine-4-carboxamide (1.0 g, 3.3 mmol) was dissolved in ethanol / water (20 mL / 5 mL). Hydroxylamine hydrochloride (255 mg, 3.66 mmol) 213 WO 2009/016498 PCT/IB2008/002046 and sodium hydroxide (213 mg, 3.66 mmol) were subsequently added, and the reaction was heated at 75 0C for 2 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an off 5 white solid (1.0 g, 90% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 4.65 min, m/z 334 (M+H). Step 3: Preparation of tert-butyl (4-(2-((((1Z)-amino(6-(((4-fluoro-3-methoxybenzvl)amino)carbonyl)-2 methylpyrimidin-4-yl)methylene)aminoloxy)-2-oxoethyl)cvclohexyl)carbamate HN--z 0 -- F0 0 C F HN -O - N-0 N\ N NH 2 10 N-(4-fluoro-3-methoxybenzyl)-6-(carbamimidoyl)-2-methylpyrimidine-4-carboxamide (500 mg, 1.50 mmol), 2-(trans-4-(tert-butoxycarbonyl)cyclohexyl)acetic acid (386 mg, 1.50 mmol), N hydroxybenzotriazole (230 mg, 1.50 mmol), and diisopropyethylamine (582 mg, 4.50 mmol) were dissolved in acetonitrile (20 mL) and dimethylacetamide (2 mL). PS-carbodiimide resin (3.49 g, 4.50 mmol) was subsequently added, and the reaction was agitated at 40 *C overnight. The reaction was 15 filtered to remove the resin, and the resin was washed with dimethylformamide. The filtrate was diluted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a white solid (700 mg, 82%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 6.23 min, m/z 517 (M+H-t-butyl). 20 Step 4: Preparation of tert-butyl (trans)-4-((3-(6-((4-fluoro-3-methoxybenzvl)carbamoyl)-2 methylpyrimidin-4-l)- 1, 2,4-oxadiazol-5-yl)methyl)cvclohexylcarbamate F 0 O -P HN -0 - N - H - N N tert-Butyl (4-(2-((((1Z)-amino(6-(((4-fluoro-3-methoxybenzyl)amino)carbonyl)-2 methylpyrimidin-4-yl)methylene)amino)oxy)-2-oxoethyl)cyclohexyl)carbamate (400 mg, 0.70 mmol) 25 was dissolved in acetonitrile (8 mL) and dimethylacetamide (4 mL). MP-carbonate resin (732 mg, 2.1 mmol) was added, and the reaction was microwaved for 15 min at 120 *C at 200W. The reaction was filtered to remove the resin, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water (3X) and saturated sodium chloride (IX) before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound 214 WO 2009/016498 PCT/IB2008/002046 as a solid (388 mg, 95%). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.): 6.76 min, m/z 577 (M+Na). Steg 5: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(5-((trans-4-aminocyclohexyl)methyl)- 1,2,4 oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide
-
N'O
NH
2 N /2 5N N 5 tert-Butyl (trans)-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1,2,4 oxadiazol-5-yl)methyl)cyclohexylcarbamate (370 mg, 0.67 mmol) was dissolved in a mixture of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for several hours before being concentrated under reduced pressure. The residue was 10 treated with saturated sodium bicarbonate, and the product was extracted into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound. LC/MS (5%-95% CH 3
CN/H
2 0, 8 min, 2 min): 4.53 min, m/z 455 (M+H). 15 Example 123 N-(4-fluoro-3-methoxybenzyl)-6-(5-((trans-4-acetamidocyclohexyl)methyl)-1,2,4-oxadiazol-3-yl) 2-methylpyrimidine-4-carboxamide F N -0 - N- 0 N N 0. N-(4-Fluoro-3-methoxybenzyl)-6-(5-((trans-4-aminocyclohexyl)methyl)- 1,2,4-oxadiazol-3-yl)-2 20 methylpyrimidine-4-carboxamide (prepared as described in Example 122) (10 mg, 0.022 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (4.45 mg, 0.0440 mmol) and acetyl chloride (1.90 mg, 0.0242 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (3x), and 25 saturated sodium chloride solution before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound (9 mg, 83% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 5.61 min, m/z 497 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.46 (t, 1 H), 8.28 (s, 1 H), 8.08 (s, 1 H), 7.49 - 7.67 (m,1 H), 7.02 - 7.19 (m, 1 H), 6.81 - 6.94 (m, 1 H), 4.39 - 4.52 (m, 2 H), 3.76 (s, 3 H), 3.31 - 3.50 (m, 1 H), 2.89 - 2.99 (m, 2 H), 30 2.78 (s, 3 H), 1.70 - 1.91 (m, 2 H), 1.71 (s, 3 H), 1.10- 1.28 (m, 7 H). 215 WO 2009/016498 PCT/IB2008/002046 Example 124 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(5-((trans-4-(methylsulfonamido)cyclohexyl)methyl) 1,2,4-oxadiazol-3-yl)pyrimidine-4-carboxamide F 0 N N ell6"' 5 N-(4-Fluoro-3-methoxybenzyl)-6-(5-((trans-4-aminocyclohexyl)methyl)-1,2,4-oxadiazol-3-yl)-2 methylpyrimidine-4-carboxamide (prepared as described in Example 122) (15 mg, 0.033 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (6.69 mg, 0.0661 mmol) and methanesulfonyl chloride (4.55 mg, 0.0397 mmol) were subsequently added, and the reaction was continued overnight at room temperature. The solvent was then removed under reduced pressure, and the residue was 10 dissolved in ethyl acetate. The organic layer was washed with water (3x), 1 N hydrochloric acid (3x), and saturated sodium chloride solution before drying over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the title compound (6.5 mg, 37% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 8 min.; 95% CH 3 CN, 2 min.) 5.70 min, m/z 534 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.47 (t, 1 H), 8.28 (s, 1 H), 7.55 - 7.72 (m,1 H), 7.02 - 7.21 (m, 2 H), 6.81 15 6.97 (m, 1 H), 4.40 - 4.52 (m, 2 H), 3.76 (s, 3 H), 2.99 - 3.08 (m, 1 H), 2.89 - 2.99 (m, 2 H), 2.85 (s, 3 H), 2.75 (s, 3 H), 1.62 - 2.02 (m, 2 H),1.11 - 1.31 (m, 7 H). Example 125 N-(4-Fluoro-3-methoxybenzyl)-6-(2-(3-hydroxypropyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 carboxamide 0 N-N, N N4 ," N F N N OH 20T N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (355 mg, 1.03 mmol), 2-bromoethanol (194 mg, 1.55 mmol), triethylamine (400 pL) and dimethylacetamide (400 25 pL) were combined. The resulting mixture was stirred at 130 *C for 2 h. The mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrate to afford a residue that upon methanol trituration provided the title compound as a white solid (25 mg, 6.2%). LC/MS (10%-90% CH 3
CN/H
2 0, 8 min): 4.94 min, m/z 388 (M+H). 'H NMR 30 (400 MHz, DMSO-d 6 ) 6 ppm 9.54 (m, 1 H), 8.42 (s, 1 H), 7.15 (td, J = 12.3, 8.4 Hz, 2 H), 6.92 (br. s, 1 H), 4.87 (t, J = 6.8 Hz, 2 H), 4.69 (br. s., 1 H), 4.51 (d, J = 5.9 Hz, 2 H), 3.82 (s, 3 H), 3.49 (d, J = 5.1 Hz, 2 H), 2.83 (s, 3 H), 2.11 (m, 2 H). 216 WO 2009/016498 PCT/IB2008/002046 Example 126 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((S)-3-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl)-2 methylpyrimidine-4-carboxamide 0 WN I - N- ' N ,N O H 5 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (104 mg, 0.303 mmol), (R)-3-bromo-2-methylpropan-1 -ol (46.4 mg, 0.303 mmol), triethylamine (400 pL) and dimethylacetamide (100 pL) were combined. The resulting mixture was stirred at 130 *C for 2 h. The 10 mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford a residue that upon methanol trituration provided the title compound as a white solid (10 mg, 7.9%). MS (ES+) m/z 416 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.50 (s, 1 H), 8.42 (s, 1 H), 7.18 (dd, J = 8.4, 1.8 Hz, 1 H), 7.14 (dd, J = 11.7, 15 8.4 Hz, 1 H), 6.91 (br. s, 1 H), 4.87 (dd, J = 13.5, 5.9 Hz, 1 H), 4.77 (t, J = 5.1 Hz, 1 H), 4.65 (dd, J = 13.5, 8.1, 1 H), 4.50 (d, J = 6.2 Hz, 2 H), 3.82 (s, 3 H), 3.38 (dt, J = 10.0, 5.1 Hz, 2 H), 2.83 (s, 3 H), 2.33 (s, 1 H), 0.86 (d, J = 7.0 Hz, 3H). Example 127 N-(4-Fluoro-3-methoxybenzyl)-6-(2-((R)-3-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl)-2 20 methylpyrimidine-4-carboxamide O N-N, N N OH N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine-4-carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-(trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 9) (104 mg, 25 0.303 mmol), (S)-3-bromo-2-methylpropan-1-ol (46.4 mg, 0.303 mmol), triethylamine (400 pL) and dimethylacetamide (100 pL) were combined. The resulting mixture was stirred at 130 *C for 2 h. The mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography. The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford a residue that upon methanol trituration 30 provided the title compound as a white solid (10 mg, 7.9%). MS (ES+) m/z 416 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.51 (s, 1 H), 8.42 (s, 1 H), 7.15 (td, J = 11.7, 8.4, Hz, 2 H), 6.91 (br. s, 1 H), 4.87 (dd, J = 13.5, 5.9 Hz, 1 H), 4.77 (t, J = 5.1 Hz, 1 H), 4.65 (dd, J = 13.5, 8.1, 1 H), 4.50 (d, J = 6.2 217 WO 2009/016498 PCT/IB2008/002046 Hz, 2 H), 3.82 (s, 3 H), 3.38 (dt, J = 10.0, 5.1 Hz, 2 H), 2.83 (s, 3 H), 2.33 (s, 1 H), 0.86 (d, J = 7.0 Hz, 3H). Example 128 N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1
H
5 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide F HN -O N/ \ - O OH N OH N N O Step 1: Preparation of N-(4-fluoro-3-methoxvbenzyl)-6-hydroxy-2-methylpyrimidine-4-carboxamide. 0 F~ N OHN I HH Methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate (prepared as described in step 2 of the 10 synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y1)-2 methylpyrimidine-4-carboxamide, Example 5) (10.0 g, 59.5 mmol), 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3- methoxybenzyl)-6-(2 ((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y1)pyrimidine-4-carboxamide, Example 1) (13.7 g, 71.4 mmol, 1.20 equiv.), and N,N-diisopropylethylamine (26 mL, 149 mmol, 2.50 equiv.) were 15 combined in methanol (120 mL). After stirring for 2 hours at reflux, the mixture was cooled to room temperature, and diluted with 1.0 N aqueous hydrochloric acid (150 mL) and water (100 mL). The resulting solid was collected by suction filtration, and the filter cake was washed with water (2 x 100 mL) and air dried for 1 h. The solid was dried under vacuum at 40 *C to provide the title compound as a tan solid (13.9 g, 80%). MS (ES+) m/z 292 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 12.75 (1 H, 20 br. s), 9.09 (1 H, t, J=6.2 Hz), 7.04 - 7.21 (2 H, m), 6.78 - 6.90 (1 H, m), 6.67 (1 H, s), 4.40 (2 H, d, J=6.2 Hz), 3.81 (3 H, s), 2.35 (3 H, s). Step 2: Preparation of N-(4-fluoro-3-methoxvbenzvl)-6-chloro-2-methvlpvrimidine-4-carboxamide, 0 0:1l N " 1C I F H N C N-(4-Fluoro-3-methoxybenzyl)-6-hydroxy-2-methylpyrimidine-4-carboxamide (10.0 g, 34.3 25 mmol) and N,N-dimethylformamide (0.66 mL, 8.58 mmol, 0.25 equiv.) were combined in tetrahydrofuran (137 mL) and the mixture was heated to 60 *C. To the mixture was added dropwise oxalyl chloride (5.1 mL, 58.4 mmol, 1.70 equiv.). After stirring for 1 hour at 60 *C, the mixture was cooled to room temperature, water (25 mL) was added dropwise, the mixture was filtered through 218 WO 2009/016498 PCT/IB2008/002046 CeliteTm, the filter cake was washed with tetrahydrofuran (100 mL), and the filtrate was evaporated to one-third the original volume. Water (150 mL) was added and the mixture was concentrated under reduced pressure to induce precipitation of the product. The solid was collected by suction filtration, the filter cake was washed with water (3 x 100 mL), and the solid was air dried for 15 hours to provide 5 the title compound as a red solid (9.50 g, 89%). MS (ES+) m/z 310 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.50 (1 H, t, J=6.2 Hz), 7.88 (1 H, s), 7.07 - 7.19 (2 H, m), 6.82 - 6.92 (1 H, in), 4.45 (2 H, d, J=6.4 Hz), 3.81 (3 H, s), 2.71 (3 H, s). Step 3: Preparation of N-(4-fluoro-3-methoxybenzvl)-2-methyl-6-(2-(trimethylsilvl)ethvnyl)pyrimidine-4 carboxamide. 0 Si 100 F ~ N -N 10T A solution of tetrahydrofuran (10.0 mL) and triethylamine (15.0 mL) was sparged with nitrogen gas for 5 minutes. To this solution was added sequentially N-(4-fluoro-3-methoxybenzyl)-6-chloro-2 methylpyrimidine-4-carboxamide (3.00 g, 9.69 mmol), dichlorobis(triphenylphosphine)palladium(II) (68 mg, 97 pmol, 0.01 equiv.), triphenylphosphine (51 mg, 0.19 mmol, 0.02 equiv.), copper (1) iodide (37 15 mg, 0.19 mmol, 0.02 equiv.), and trimethylsilylacetylene (2.2 mL, 15.5 mmol, 1.60 equiv.). After stirring for 3 hours at 50 *C, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, and concentrated under reduced pressure to give a red oil. Purification by silica gel chromatography (gradient 5:1 heptane/EtOAc to 2:1 heptane/EtOAc) provided the title compound as a viscous, yellow oil (2.60 g, 72%). LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 4.12 min, m/z 372 (M+H). 20 Step 4: Preparation of N-(4-fluoro-3-methoxvbenzvl)-6-ethynyl-2-methylpyrimidine-4-carboxamide. 0 F N N To a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-(trimethylsilyl)ethynyl)pyrimidine 4-carboxamide (2.60 g, 7.00 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added potassium fluoride (447 mg, 7.70 mmol, 1.10 equiv.). After stirring for 2 hours at room temperature, 25 the mixture was concentrated under reduced pressure to remove the tetrahydrofuran, diluted with ethyl acetate (50 mL), and washed with pH 7.0 aqueous phosphate buffer. The layers were separated and the aqueous layer was washed with ethyl acetate (1x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (2.06 g, >95%). LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 3.24 min, m/z 300 (M+H). 219 WO 2009/016498 PCT/IB2008/002046 Step 5: Preparation of ((2S,5R)-5-((trifluoromethylsulfonvloxy)methyl)-1,4-dioxan-2-yi)methvl4 methylbenzenesulfonate. 0 0
F
3 C' 0 60 ((2S,5S)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as 5 described in step 1 of the synthesis of N-(3-methoxybenzy1 )-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4 dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 62) (5.0 g, 16.5 mmol) and pyridine (1.4 mL, 17.3, 1.05 equiv.) were combined in 70 mL dichloromethane, the resulting solution was cooled in a methanol/ice bath, and a solution of trifluoromethanesulfonic anhydride (2.9 mL, 17.3 mmol, 1.05 equiv.) in dichloromethane (10 mL) was added dropwise via cannula. After 10 warming to room temperature, the mixture was diluted with dichloromethane (150 mL) and treated with 1.0 N aqueous hydrochloric acid (40 mL). The layers were separated and the aqueous layer was washed with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (6.89 g, >95%). 15 Step 6: Preparation of ((2S.5S)-5-((4-(6-((4-fluoro-3-methoxvbenzvl)carbamoyl)-2-methylpyrimidin-4 yl)-1 H-1,2,3-triazol-1 -vl)methyl)- 1 ,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate. F 0 -0 HN O I N-0 0 sR N N 0 ((2S,5R)-5-((Trifluoromethylsulfonyloxy)methyl)- 1 ,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (100 mg, 0.23 mmol) and sodium azide (16 mg, 0.24 mmol, 1.05 equiv.) were 20 combined in tetrahydrofuran (0.8 mL), tert-butanol (0.4 mL), and water (0.4 mL). After stirring for 1 hour at room temperature, the reaction vessel was charged sequentially with N-(4-fluoro-3 methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4-carboxamide (69 mg, 0.23 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (23 pL, 0.023 mmol, 0.10 equiv.), and 0.30 M aqueous copper (11) sulfate (17 pL, 0.005 mmol, 0.02 equiv.). After stirring for 15 hours at room temperature, the mixture was 25 diluted with ethyl acetate and washed with 50% aqueous sodium chloride. The layers were separated and the aqueous layer was washed with ethyl acetate (3x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a dark, orange oil. Purification by silica gel chromatography (gradient 1:1 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (142 mg, >95%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 3.07 min, m/z 30 627 (M+H). 220 WO 2009/016498 PCT/IB2008/002046 Step 7: Prenaration of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yI)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. F - / N O -O N ~ ~ O -N O 0 - OH N N O110 ((2S,5S)-5-((4-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1 H-1,2,3 5 triazol- 1 -yl)methyl)- 1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (75 mg, 0.12 mmol) and tetrabutylammonium acetate (40 mg, 0.13 mmol, 1.10 equiv.) were combined in dimethylformamide (1.0 mL). After stirring for 1 hour at 65 *C, the mixture was cooled to room temperature, and the reaction vessel was charged sequentially with water (250 pL) and 1.0 N aqueous sodium hydroxide (144 pL, 0.144 mmol, 1.20 equiv.). After stirring for 20 minutes at room temperature, the mixture was 10 diluted with ethyl acetate (10 mL) and washed with 50% aqueous sodium chloride (2 x 3 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange oil. Purification by silica gel chromatography (gradient 100% EtOAc to 5% MeOH/EtOAc) provided the title compound as a white solid (40 mg, 71%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.01 min, m/z 473 (M+H). 'H NMR (400 MHz, CD 3 0D) 6 ppm 8.65 (1 H, s), 8.47 (1 H, s), 7.13 (1 H, 15 dd, J=8.3, 1.8 Hz), 7.03 (1 H, dd, J=1 1.4, 8.3 Hz), 6.86 - 6.97 (1 H, m), 4.60 - 4.70 (1 H, m), 4.58 (3 H, s), 4.45 - 4.55 (1 H, m), 3.92 - 4.01 (2 H, m), 3.88 (1 H, d, J=11.1 Hz), 3.86 (3 H, s), 3.51 - 3.59 (1 H, m), 3.47 - 3.51 (2 H, m), 3.41 - 3.48 (1 H, m), 3.33 - 3.41 (1 H, m), 2.77 (3 H, s). Example 129 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2 20 methylpyrimidine-4-carboxamide F HN 0 O -O N N N N N " O Step 1: Preparation of methyl 2-m ethyl-6-(2-(trim ethylsilyl)ethynyl)pyrimidine-4-carboxylate. I " O Si O'J N N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-2 25 methyl-6-(2-(trimethylsilyl)ethynyl)pyrimidine-4-carboxamide (step 3, Example 128) by reaction of methyl 6-chloro-2-methylpyrimidine-4-carboxylate (prepared as described in step 3 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y1)-2-methylpyrimidine 221 WO 2009/016498 PCT/IB2008/002046 4-carboxamide, Example 5) (1.00 g, 5.36 mmol), dichlorobis(triphenylphosphine)palladium(ll) (38 mg, 54 pmol, 0.01 equiv.), triphenylphosphine (28 mg, 0.11 mmol, 0.02 equiv.), copper (1) iodide (20 mg, 0.11 mmol, 0.02 equiv.), and trimethylsilylacetylene (1.2 mL, 8.50 mmol, 1.60 equiv.). Purification by silica gel chromatography (gradient 3:1 heptane/EtOAc to 2:1 heptane/EtOAc) provided the title 5 compound as a tan solid (1.15 g, 86%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.91 min, m/z 249 (M+H). Step 2: Preparation of methyl 6-ethynyl-2-methylpyrimidine-4-carboxylate. 0 N , N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-6 10 ethynyl-2-methylpyrimidine-4-carboxamide (step 4, Example 128) by reaction of methyl 2-methyl-6-(2 (trimethylsilyl)ethynyl)pyrimidine-4-carboxylate (100 mg, 0.40 mmol) and potassium fluoride (26 mg, 0.44 mmol, 1.10 equiv.) to afford the title compound as an orangish-brown solid (70 mg, >95%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 1.20 min, m/z 177 (M+H). Step 3: Preparation of (9H-fluoren-9-vl)methyl (S)-2-(hydroxvmethyl)morpholine-4-carboxylate. O / \ HO N O 15 tert-Butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (1.0 g, 4.60 mmol) and 4.0 M hydrochloric acid in 1,4-dioxane (5.0 mL, 20.0 mmol, 4.35 equiv.) were combined and the solution was stirred at room temperature for 30 minutes. The solvent was evaporated and to the crude residue was added sequentially tetrahydrofuran (10 mL), water (5.0 mL), sodium bicarbonate (1.16 g, 13.8 mmol, 20 3.0 equiv.), and 9-fluorenylmethyl chloroformate (1.19 g, 4.60 mmol, 1.00 equiv.). After stirring for 15 h at room temperature, the tetrahydrofuran was evaporated under reduced pressure and the mixture was diluted with ethyl acetate (25 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (1.56 g, >95%). 222 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of (9H-fluoren-9-yl)methyl (S)-2-((trifluoromethylsulfonyloxy)methyl)morpholine-4 carboxylate. 0 o
F
3 C-S-O N 0 The title compound was prepared in a similar manner to ((2S,5R)-5 5 ((trifluoromethylsulfonyloxy)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 5, Example 128) by reaction of (9H-fluoren-9-yl)methyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (1.25 g, 3.68 mmol), pyridine (313 pL, 3.87 mmol, 1.05 equiv.), and trifluoromethanesulfonic anhydride (0.65 mL, 3.87 mmol, 1.05 equiv.) to afford the title compound as a light tan solid (1.68 g, >95%). Step 5: Preparation of methyl 6-(1-(((S)-4-(((9H-fluoren-9-yl)methoxy)carbonl)morpholin-2-yl)methyl) 10 1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxylate. O:
---
N NI NN N NN 0 0 The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1 H-1,2,3-triazol- 1 -yl)methyl)- 1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (9H-fluoren-9-yl)methyl (S)-2 15 ((trifluoromethylsulfonyloxy)methyl)morpholine-4-carboxylate (140 mg, 0.30 mmol), sodium azide (20 mg, 0.31 mmol, 1.05 equiv.), methyl 6-ethynyl-2-methylpyrimidine-4-carboxylate (52 mg, 0.30 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (30 pL, 0.030 mmol, 0.10 equiv.), and 0.30 M aqueous copper (II) sulfate (20 pL, 0.006 mmol, 0.02 equiv.). Purification by silica gel chromatography (gradient 1:1 heptane/EtOAc to 100% EtOAc) provided the title compound as a tan solid (113 mg, 20 71%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.99 min, m/z 541 (M+H). Step 6: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-vl)methyl)- 1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. F
-
HN 0 -0 NN N N NI Methyl 6-(1 -(((S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)morpholin-2-yl)methyl)- 1 H- 1,2,3 25 triazol-4-yl)-2-methylpyrimidine-4-carboxylate (49 mg, 91 pmol), 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3- methoxybenzyl)-6-(2 ((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (52 mg, 223 WO 2009/016498 PCT/IB2008/002046 0.27 mmol, 3.00 equiv.), and triethylamine (51 pL, 0.36 mmol, 4.00 equiv.) were combined in N,N dimethylacetamide (1.0 mL). After stirring for 1 hour at 65 *C, the mixture was cooled to room temperature, and to the mixture was added sequentially dichloromethane (1.0 mL), triethylamine (76 pL, 0.54 mmol, 6.00 equiv.), and acetyl chloride (32 pL, 0.45 mmol, 5.00 equiv.). After stirring for 1 5 hour at room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate (5 mL), and washed with pH 7.0 aqueous phosphate buffer (2 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Partial purification by silica gel chromatography (gradient 1:2 heptane/EtOAc to 100% EtOAc to 5% 10 MeOH/EtOAc) provided an oily residue, which was further purified by reverse-phase HPLC to afford the title compound as a white solid (7 mg, 16%). MS (ES+) m/z 484 (M+H). 'H NMR (400 MHz, DMSO-d) 6 9.39 (1 H, t, J=5.9 Hz), 8.80 (1 H, d, J=11.9 Hz), 8.34 (1 H, s), 7.17 - 7.21 (1 H, m), 7.14 (1 H, dd, J=1 1.7, 8.6 Hz), 6.81 - 6.98 (1 H, m), 4.63 - 4.77 (1 H, m), 4.54 - 4.63 (1 H, m), 4.49 (2 H, d, J=6.2 Hz), 4.21 (1 H, dd, J=86.2, 13.0 Hz), 3.85 - 3.98 (2 H, m), 3.82 (3 H, s), 3.39 - 3.71 (1 H, m), 15 2.92 - 3.23 (1 H, m), 2.75 (3 H, s), 2.52 - 2.73 (1 H, m), 2.02 (3 H, d, J=1 1.3 Hz). Example 130 N-(3-Methoxybenzyl)-2-methyl-6-(1 -((S)-morpholin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl)pyrimidine-4 carboxamide HN O H -O N N N N D 20 Step 1: Preparation of 6-(1-(((S)-4-(((9H-fluoren-9-vl)methoxv)carbonvl)morpholin-2-vl)methyl)-1H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxylic acid. HO N, N -N N O 0 Methyl 2-methyl-6-(2-(trimethylsilyl)ethynyl)pyrimidine-4-carboxylate (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)-1 H 25 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 129) (200 mg, 0.81 mmol) was dissolved in tetrahydrofuran (0.90 mL), tert-butanol (0.90 mL), and water (0.90 mL), and to this mixture was added 2.0 N aqueous lithium hydroxide (423 pL, 0.85 mmol, 1.05 equiv.). In a separate reaction vessel, (9H-fluoren-9-yl)methyl (S)-2-((trifluoromethylsulfonyloxy)methyl)morpholine-4-carboxylate (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((S)-4 30 acetylmorpholin-2-yl)methyl)- 1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 129) 224 WO 2009/016498 PCT/IB2008/002046 (380 mg, 0.81 mmol, 1.00 equiv.) and sodium azide (55 mg, 0.85 mmol, 1.05 equiv.) were combined in tetrahydrofuran (0.90 mL), tert-butanol (0.90 mL), and water (0.90 mL). After stirring for 2 hours at room temperature, both crude reaction mixtures were combined into a single reaction vessel. To this mixture was added sequentially 1.0 M aqueous sodium ascorbate (81 pL, 0.081 mmol, 0.10 equiv.), 5 and 0.30 M aqueous copper (11) sulfate (54 pL, 0.016 mmol, 0.02 equiv.). After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (4 mL) and washed with 2.0 N aqueous sodium hydroxide (0.5 mL). The layers were separated, the aqueous layer was acidified with 1.0 N aqueous hydrochloric acid (1.2 mL), and extracted with ethyl acetate (3 x 2 mL) and dichloromethane (3 x 2 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated 10 under reduced pressure to provide the crude title compound as a purple solid (424 mg) that was used in subsequent reactions without further purification. LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.60 min, m/z 527 (M+H). Step 2: Preparation of (2S)-(9H-fluoren-9-yl)methyl 2-((4-(6-((3-methoxvbenzvl)carbamovl)-2 methylpyrimidin-4-yl)- 1H- 1,2,3-triazol- 1 -ylmethyl)morpholine-4-carboxylate. HN -O N N N N'r N 15 0 6-(1 -(((S)-4 -(((9H-Fluoren-9-yl)methoxy)carbonyl)morpholin-2-yl)methyl)- H-1,2,3-triazol-4-yl) 2-methylpyrimidine-4-carboxylic acid (200 mg, 0.38 mmol), 3-methoxybenzylamine (54 pL, 0.42 mmol, 1.10 equiv.), N,N-diisopropylethylamine (79 pL, 0.42 mmol, 1.20 equiv.), and 0-(7-azabenzotriazol-1 yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (188 mg, 0.49 mmol, 1.30 equiv.) were 20 combined in N,N-dimethylformamide (2.5 mL). After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL), and washed with pH 7.0 aqueous phosphate buffer (3 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 2 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue. Purification by silica gel chromatography (gradient 1:1 25 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (192 mg, 78%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 3.43 min, m/z 646 (M+H). Step 3: Preparation of N-(3-methoxvbenzvl)-2-methyl-6-( 1-((S)-morpholin-2-ylmethyl)- 1 H- 1,2,3-triazol 4-yl)pyrimidine-4-carboxamide. N H -O NaN N N N 30 (2S)-(9H-Fluoren-9-yl)methyl 2-((4-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl) 1H-1,2,3-triazol-1-yl)methyl)morpholine-4-carboxylate (192 mg, 0.30 mmol) and piperidine (60 pL, 225 WO 2009/016498 PCT/IB2008/002046 0.60 mmol, 2.0 equiv.) were combined in N,N-dimethylformamide (1.2 mL). After stirring for 5 minutes at room temperature, the mixture was concentrated under reduced pressure to afford the crude title compound as an oil that was used in subsequent reactions without further purification. LC/MS (10% 90% CH 3
CN/H
2 0, 5 min): 1.62 min, m/z 424 (M+H). 5 Example 131 N-(3-Methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide N 0 O -O Nz N N N N NN N N-(3-Methoxybenzyl)-2-methyl-6-(1 -((S)-morpholin-2-ylmethyl)-1 H-1,2,3-triazol-4 10 yl)pyrimidine-4-carboxamide (prepared as described in Example 130) (63 mg, 0.15 mmol), triethylamine (83 pL, 0.60 mmol, 4.00 equiv.), and acetyl chloride (32 pL, 0.45 mmol, 3.00 equiv.) were combined in dichloromethane (1.5 mL). After stirring for 1 hour at room temperature, methanol (0.5 mL) was added and the mixture was concentrated under reduced pressure to give a salty slurry. Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the 15 title compound as an off-white foam (41 mg, 60%). MS (ES+) m/z 466 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.38 (1 H, t, J=6.3 Hz), 8.80 (1 H, d, J=12.3 Hz), 8.34 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.89 - 6.98 (2 H, m), 6.82 (1 H, dd, J=8.3, 1.9 Hz), 4.65 - 4.79 (1 H, m), 4.52 - 4.64 (1 H, m), 4.50 (2 H, d, J=6.2 Hz), 4.21 (1 H, dd, J=86.1, 12.7 Hz), 3.77 - 3.99 (3 H, m), 3.74 (3 H, s), 3.65 (1 H, d, J=14.3 Hz), 3.33 - 3.51 (1 H, m), 2.94 - 3.21 (1 H, m), 2.75 (3 H, s), 2.02 (3 H, d, J=1 1.5 Hz). 20 Example 132 N-(3-Methoxybenzyl)-2-methyl-6-(1 -(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-1 H-1,2,3 triazol-4-yl)pyrimidine-4-carboxamide o / HN OZZS0 -O N N N N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-(1-(((S)-4 25 acetylmorpholin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (Example 131) by reaction of N-(3-methoxybenzyl)-2-methyl-6-(1 -((S)-morpholin-2-ylmethyl)- 1 H- 1,2,3-triazol-4 yl)pyrimidine-4-carboxamide (prepared as described in Example 130) (63 mg, 0.15 mmol), triethylamine (83 pL, 0.60 mmol, 4.00 equiv.), and methanesulfonyl chloride (34 pL, 0.45 mmol, 3.00 equiv.) to afford the title compound as an off-white foam (48 mg, 65%). MS (ES+) m/z 502 (M+H). 'H 30 NMR (400 MHz, DMSO-d 6 ) 6 9.38 (1 H, t, J=6.4 Hz), 8.84 (1 H, s), 8.34 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.88 - 6.98 (2 H, m), 6.82 (1 H, dd, J=8.2, 2.0 Hz), 4.68 - 4.76 (1 H, m), 4.55 - 4.65 (1 H, m), 4.50 226 WO 2009/016498 PCT/IB2008/002046 (2 H, d, J=6.2 Hz), 3.98 - 4.08 (1 H, m), 3.95 (1 H, d, J=1 1.0 Hz), 3.74 (3 H, s), 3.48 - 3.63 (2 H, m), 3.32 - 3.40 (1 H, m), 2.92 (3 H, s), 2.80 - 2.90 (1 H, m), 2.75 (3 H, s), 2.68 (1 H, dd, J=1 1.4, 10.2 Hz). Example 133 N-(3-Methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4 5 yl)-2-methylpyrimidine-4-carboxamide HN -0 /\ NN 0 -'-KN O N I OH N0 0 Step 1: Preparation of methyl 2-methyl-6-(1-(((2S,5S)-5-((tosyloxy)methyl)-1,4-dioxan-2-yl)methyl)-1H 1,2,3-triazol-4-yl)pyrimidine-4-carboxylate. 0 N OO 10 Methyl 2-methyl-6-(2-(trimethylsilyl)ethynyl)pyrimidine-4-carboxylate (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)- 1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 129) (30 mg, 0.12 mmol) was dissolved in tetrahydrofuran (0.20 mL), tert-butanol (0.20 mL), and water (0.20 mL), and to this mixture was added potassium fluoride (7 mg, 0.12 mmol, 1.00 equiv.). In a separate reaction vessel, ((2S,5R)-5 15 ((trifluoromethylsulfonyloxy)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 5 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (50 mg, 0.12 mmol, 1.00 equiv.) and sodium azide (8 mg, 0.12 mmol, 1.00 equiv.) were combined in tetrahydrofuran (0.2 mL), tert-butanol (0.2 mL), and water (0.2 mL).. After stirring for 1 hour at room 20 temperature, both crude reaction mixtures were combined into a single reaction vessel. To this mixture was added sequentially 1.0 M aqueous sodium ascorbate (12 pL, 0.012 mmol, 0.10 equiv.), and 0.30 M aqueous copper (11) sulfate (8 pL, 0.002 mmol, 0.02 equiv.). After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (4 mL) and washed with saturated aqueous sodium chloride (1 mL). The layers were separated and the aqueous layer was washed with 25 ethyl acetate (2 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide an orange oil. Purification by silica gel chromatography (gradient 1:1 heptane/EtOAc to 100% EtOAc) provided the title compound as a yellow solid (59 mg, >95%). LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.50 min, m/z 504 (M+H). 227 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of 2-methyl-6-(1 -(((2S,5S)-5-((tosyloxy)methyl)- 1,4-dioxan-2-yl)methyl)- 1H-1,2,3 triazol-4-yl)pyrimidine-4-carboxylic acid. 0 HO NIS N NN O 0 N Noe '-O Methyl 2-methyl-6-(1-(((2S,5S)-5-((tosyloxy)methyl)-1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4 5 yl)pyrimidine-4-carboxylate (59 mg, 0.12 mmol) was dissolved in tetrahydrofuran (0.80 mL), and water (0.40 mL), and to this mixture was added 2.0 N aqueous lithium hydroxide (65 pL, 0.13 mmol, 1.08 equiv.). After stirring for 5 minutes at room temperature, the solution was neutralized with 1.0 N aqueous hydrochloric acid (130 pL, 0.13 mmol, 1.08 equiv.). The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (4 mL) and methanol (2 mL), dried over 10 sodium sulfate, filtered and concentrated under reduced pressure to afford the crude title compound as an orange solid (57 mg) that was used in subsequent reactions without further purification. LC/MS (10%-90% CH 3
CN/H
2 0, 5 min): 2.13 min, m/z 490 (M+H). Step 3: Preparation of ((2S, 5S)-5-((4-(6-(3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)- 1 H 1,2,3-triazol-1-vl)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate.
--
O N 0 H N N 0O'S 15 N 2-Methyl-6-(1-(((2S,5S)-5-((tosyloxy)methyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4 yl)pyrimidine-4-carboxylic acid (108 mg, 0.22 mmol), 3-methoxybenzylamine (30 pL, 0.23 mmol, 1.05 equiv.), N,N-diisopropylethylamine (40 pL, 0.23 mmol, 1.05 equiv.), and O-(7-azabenzotriazol-1-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate (88 mg, 0.23 mmol, 1.05 equiv.) were combined in 20 NN-dimethylformamide (1.5 mL). After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL) and washed with 10% aqueous sodium bisulfate (3 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 2 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue. Purification by silica gel chromatography (gradient 1:2 heptane/EtOAc to 100% EtOAc 25 to 10% MeOH/EtOAc) provided the title compound as a white solid (131 mg, >95%). LC/MS (10% 90% CH 3
CN/H
2 0, 5 min): 3.02 min, m/z 609 (M+H). 228 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of N-(3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yI)methyl) 1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. 0 / HN O OH The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-6-(1 5 (((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4 carboxamide (step 7, Example 128) by reaction of ((2S,5S)-5-((4-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (131 g, 0.22 mmol), tetrabutylammonium acetate (71 mg, 0.24 mmol, 1.10 equiv.), and 1.0 N aqueous sodium hydroxide (260 pL, 0.26 mmol, 1.20 equiv.). Purification by silica gel chromatography 10 (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (50 mg, 51%), MS (ES+) m/z 455 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.38 (1 H, t, J=6.4 Hz), 8.80 (1 H, s), 8.33 (1 H, s), 7.24 (1 H, t, J=8.1 Hz), 6.88 - 6.99 (2 H, m), 6.82 (1 H, dd, J=8.1, 2.0 Hz), 4.67 (1 H, t, J=5.6 Hz), 4.55 - 4.63 (1 H, m), 4.43 - 4.54 (3 H, n), 3.87 - 4.01 (2 H, m), 3.77 - 3.85 (1 H, m), 3.74 (3 H, s), 3.32 - 3.47 (4 H, m), 2.75 (3 H, s). 15 Example 134 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide F - HN 0 N N - o N _ NN < ~ H Step 1: Preparation of ((trans)-4-(tert-butoxvcarbonl)cclohexyl)methVl 2,2,2-trifluoroethanesulfonate. 0 0 N 0 20 H Commercially available tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (2.00 g, 8.72 mmol), 2,2,2-trifluoroethanesulfonyl chloride (1.2 mL, 11.0 mmol, 1.20 equiv.), and N,N diisopropylethylamine (2.0 mL, 11.0 mmol, 1.20 equiv.) were combined in dichloromethane (35 mL). After stirring for 1 hour at 0 *C, the mixture was concentrated under reduced pressure, and the salty 25 residue was partitioned between ethyl acetate (100 mL) and 1.0 N aqueous hydrochloric acid (20 mL). The layers were separated and the organic layer was washed with 1.0 N aqueous hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by 229 WO 2009/016498 PCT/IB2008/002046 recrystallization (1:2 heptane/EtOAc) provided the title compound as a white needles (2.29 g, 70%). 'H NMR (400 MHz, CDCl 3 ) 6 4.40 (1 H, br. s.), 4,15 (2 H, d, J=6.5 Hz), 3.89 (2 H, q, J=8.7 Hz), 3.40 (1 H, br. s.), 1.98 - 2.16 (2 H, m), 1.80 - 1.93 (2 H, n), 1.66 - 1.79 (1 H, m), 1.44 (9 H, s), 1.05 - 1.20 (4 H, m). Step 2: Preparation of tert-butyl (trans)-4-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 5 methylpyrimidin-4-yl)-IH-1,2,3-triazol-1 -yl)methyl)cyclohexvlcarbamate. F N -O NzN H N N O ((trans)-4-(tert-Butoxycarbonyl)cyclohexyl)methy 2,2,2-trifluoroethanesulfonate (450 mg, 1.20 mmol) and sodium azide (80 mg, 1.22 mmol, 1.02 equiv.) were combined in N,N-dimethylformamide (1.0 mL). After stirring for 18 hours at room temperature, the reaction vessel was charged sequentially 10 with N,N-dimethylformamide (3.0 mL), water (1.0 mL), N-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2 methylpyrimidine-4-carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3 methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide, Example 128) (305 mg, 1.20 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (120 pL, 0.12 mmol, 0.10 equiv.), and 0.30 M aqueous copper (11) sulfate (80 pL, 15 0.024 mmol, 0.02 equiv.). After stirring for 23 hours at room temperature, to the reaction mixture was added sequentially N,N-dimethylformamide (2.0 mL), 1.0 M aqueous sodium ascorbate (120 pL, 0.12 mmol, 0.10 equiv.), and 0.30 M aqueous copper (Il) sulfate (80 pL, 0.024 mmol, 0.02 equiv.). After stirring for 6 hours at room temperature, the mixture was poured with vigorous stirring into ice-cold water (150 mL). The precipitate was collected by suction filtration, washed with water (3x), dissolved 20 in ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reddish-orange amorphous solid was dissolved in 5% methanol/ethyl acetate, filtered through a short pad of silica, and concentrated under reduced pressure. Purification by recrystallization (2:3 heptane/EtOAc) provided the title compound as a pale orange solid (504 mg, 76%). LC/MS (5% 100% CH 3
CN/H
2 0, 5 min): 3.71 min, m/z 554 (M+H). 25 Step 3: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((trans)-4-aminocyclohexyl)methyl)-1H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. F HN O -0 NN N2 N I ,, / _N N 1 tert-Butyl (trans)-4-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1H 1,2,3-triazol-1-yl)methyl)cyclohexylcarbamate (497 mg, 0.90 mmol) and 4.0 N hydrochloric acid in 1,4 30 dioxane (3.6 mL, 14.4 mmol, 16.0 equiv,) were combined in 1,4-dioxane (4.0 mL). After stirring for 18 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol, concentrated under reduced pressure, and dried under high vacuum to afford 230 WO 2009/016498 PCT/IB2008/002046 the hydrochloride salt form of title compound as a white solid (440 mg, >95%) that was used in subsequent reactions without further purification. LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 2.74 min, m/z 454 (M+H). Example 135 5 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((trans)-4-acetamidocyclohexyl)methyl)-1 H-1,2,3-triazol-4 yl)-2-methylpyrimidine-4-carboxamide F \ /1HN 0 F0 N -O NN N N H N ''' The hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((trans)-4-aminocyclohexyl) methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 10 134) (440 mg, 0.90 mmol), triethylamine (376 pL, 2.70 mmol, 3.00 equiv.), and acetyl chloride (77 pL, 1.08 mmol, 1.20 equiv.) were combined in dichloromethane (5.0 mL). After stirring for 1 hour at room temperature, methanol (2 mL) was added and the mixture was diluted with dichloromethane (20 mL) and water (5 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (gradient 15 100% EtOAc to 20% MeOH/EtOAc) provided the title compound as a white solid (353 mg, 79%). LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 3.17 min, m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.46 (1 H, t, J=6.4 Hz), 8.90 (1 H, s), 8.33 (1 H, s), 7.71 (1 H, d, J=7.9 Hz), 7.10 - 7.23 (2 H, m), 6.84 6.95 (1 H, m), 4.49 (2 H, d, J=6.3 Hz), 4.33 (2 H, d, J=7.2 Hz), 3.82 (3 H, s), 2.75 (3 H, s), 1.82 - 1.94 (1 H, m), 1.75 - 1.82 (2 H, m), 1.75 (3 H, s), 1.47 - 1.63 (2 H, m), 1.00 - 1.18 (4 H, m). 20 Example 136 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide F N 0 -O N N N N \N OH /:_N N " NO The hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1 -(((trans)-4-aminocyclohexyl) 25 methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described Example 134) (224 mg, 0.46 mmol), triethylamine (160 ,L, 1.14 mmol, 2.50 equiv.), and 2-acetoxyacetyl chloride (59 pL, 0.55 mmol, 1.20 equiv.) were combined in dichloromethane (10 mL). After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure. To the salty residue were added sequentially tetrahydrofuran (4.0 mL) and 2.0 N aqueous lithium hydroxide (2.0 30 mL, 4.00 mmol, 8.70 equiv.). After stirring for 1 hour at room temperature, the mixture was diluted with ethyl acetate (20 mL) and water (5 mL). The layers were separated and the organic layer was dried 231 WO 2009/016498 PCT/IB2008/002046 over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (185 mg, 81%). MS (ES+) m/z 512 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.47 (1 H, t, J=6.3 Hz), 8.90 (1 H, s), 8.33 (1 H, s), 7.47 (1 H, d, J=8.2 Hz), 7.11 - 7.21 (2 H, m), 6.90 (1 H, ddd), 5.41 (1 5 H, t, J=5.8 Hz), 4.49 (2 H, d, J=6.4 Hz), 4.34 (2 H, d, J=7.1 Hz), 3.82 (3 H, s), 3.75 (2 H, d, J=5.7 Hz), 3.48 - 3.64 (1 H, m), 2.74 (3 H, s), 1.80 - 1.98 (1 H, m), 1.73 (2 H, d, J=1 1.2 Hz), 1.56 (2 H, d, J=1 1.9 Hz), 1.19 - 1.36 (2 H, m), 1.00 - 1.19 (2 H, m). Example 137 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 R,3S)-3-aminocyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)-2 10 methylpyrimidine-4-carboxamide F N NH2 NI - N Step 1: Preparation of ((1R,3S)-3-(tert-butoxycarbonyl)cyclopentyl)methvl 2,2,2 trifluoroethanesulfonate. 00 H
F
3 C& S, N O o1< 0 15 tert-Butyl (1 S,3R)-3-(hydroxymethyl)cyclopentylcarbamate (prepared from commercially available 1-(R)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one according to the method described by Shuto and coworkers, see Kudoh, T. et al. J. Am. Chem. Soc. 2005, 127, 8846-8855) (150 mg, 0.70 mmol), 2,2,2-trifluoroethanesulfonyl chloride (82 pL, 0.73 mmol, 1.05 equiv.), and N,N-diisopropylethylamine (140 pL, 0.80 mmol, 1.15 equiv.) were combined in dichloromethane (3.0 mL). After stirring for 30 20 minutes at 0 *C, the mixture was diluted with dichloromethane (15 mL) and 10% aqueous sodium bisulfate (5 mL). The layers were separated and the aqueous layer was washed with dichloromethane (1x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (gradient 4:1 heptane/EtOAc to 2:1 heptane/EtOAc) provided the title compound as a white solid (206 mg, 82%). 1 H NMR (400 MHz, 25 CDCl 3 ) 6 4.50 (1 H, br. s.), 4.28 (2 H, d, J=6.4 Hz), 3.97 (1 H, br. s.), 3.90 (2 H, q, J=8.8 Hz), 2.33 2.46 (1 H, m), 2.20 - 2.32 (1 H, m), 1,95 - 2.09 (1 H, m), 1.77 - 1.91 (1 H, m), 1.46 - 1.58 (2 H, m), 1.45 (9 H, s), 1.10 - 1.23 (1 H, m). Step 2: Preparation of tert-butyl (1 S,3R)-3-(azidomethyl)cvclopentylcarbamate. H
N
3 N O 30 ((1 R,3S)-3-(tert-Butoxycarbonyl)cyclopentyl)methyl 2,2,2-trifluoroethanesulfonate (125 mg, 0.35 mmol) and sodium azide (35 mg, 0.54 mmol, 1.54 equiv.) were combined in N,N 232 WO 2009/016498 PCT/IB2008/002046 dimethylformamide (0.90 mL). After stirring for 1 hour at 60 *C, the mixture was cooled to room temperature and diluted with ethyl acetate (10 mL) and 50% aqueous sodium chloride (2 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 5 Purification by silica gel chromatography (gradient 4:1 heptane/EtOAc to 2:1 heptane/EtOAc) provided the title compound as a colorless oil (83 mg, >95%). Step 3: Preparation of tert-butyl (1 S,3R)-3-((4-(6-((4-fluoro-3-methoxvbenzyl)carbamoyl)-2 methylpyrimidin-4-vl)-1 H-1,2,3-triazol-1 -yl)methvl)cyclopentylcarbamate. F _5 _HN 00 HN O HN -O/ NN 0 N N N 10 tert-Butyl (1S,3R)-3-(azidomethyl)cyclopentylcarbamate (75 mg, 0.31 mmol), N-(4-fluoro-3 methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4-carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (93 mg, 0.31 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (31 pL, 0.031 mmol, 0.10 equiv.), and 0.30 M aqueous 15 copper (11) sulfate (20 pL, 0.006 mmol, 0.02 equiv.) were combined in tetrahydrofuran (0.50 mL), tert butanol (0.50 mL), and water (0.50 mL). After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium chloride (2 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 20 Purification by silica gel chromatography (gradient 4:1 heptane/EtOAc to 100% EtOAc) provided the title compound as an off-white solid (136 mg, 81%). LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 3.78 min, m/z 484 (M - 2-Me-propene + H). Step 4: Preparation of N-(4-fluoro-3-methoxvbenzyl)-6-(1 -(((1 R,3S)-3-aminocyclopentvl)methyl)-1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. F HN 0NH2 0 / NNNH NI -O N 25 tert-Butyl (1 S,3R)-3-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1 H 1,2,3-triazol-1-yl)methyl)cyclopentylcarbamate (136 mg, 0.25 mmol) was dissolved in 4.0 N hydrochloric acid in methanol (1.5 mL, 6.00 mmol, 24.2 equiv.). After stirring for 18 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 30 methanol, concentrated under reduced pressure, and dried under high vacuum to afford the hydrochloride salt form of title compound as a white solid (118 mg, >95%) that was used in 233 WO 2009/016498 PCT/IB2008/002046 subsequent reactions without further purification. LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 2.73 min, m/z 440 (M+H). Example 138 N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((1R,3S)-3-acetamidocyclopentyl)methyl)-1H-1,2,3-triazol-4 5 yl)-2-methylpyrimidine-4-carboxamide -F N HN NI The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-(1-(((S)-4 acetylmorpholin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (Example 131) by reaction of the hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((1R,3S)-3 10 aminocyclopentyl)methyl)- 1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 137) (39 mg, 0.089 mmol), triethylamine (35 pL, 0.25 mmol, 2.80 equiv.), and acetyl chloride (15 pL, 0.21 mmol, 2.40 equiv.). Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (27 mg, 63%). MS (ES+) m/z 482 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 9.39 (1 H, t, J=6.2 Hz), 8.89 (1 H, s), 8.34 15 (1 H, s), 7.81 (1 H, d, J=7.3 Hz), 7.18 (1 H, dd, J=8.6, 1.6 Hz), 7.14 (1 H, dd, J=12.0, 8.5 Hz), 6.85 6.96 (1 H, m), 4.50 (2 H, d, J=6.2 Hz), 4.46 (2 H, d, J=7.3 Hz), 3.92 - 4.05 (1 H, m), 3.83 (3 H, s), 2.75 (3 H, s), 1.91 - 2.01 (1 H, m), 1.78 - 1.88 (1 H, m), 1.76 (3 H, s), 1.57 - 1.70 (1 H, m), 1.37 - 1.54 (2 H, m), 1.07 - 1.22 (1 H, m). Example 139 20 N-(4-fluoro-3-methoxybenzyl)-6-(1-(((1R,3S)-3-(2-hydroxyacetamido)cyclopentyl)methyl)-1H 1,2,3-triazol-4-yI)-2-methylpyrimidine-4-carboxamide F- /H 0 0 HN HN -O N N OH N />-N N,5 The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-6-(1 (((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4 25 carboxamide (Example 136) by reaction of the hydrochloride salt form of N-(4-fluoro-3 methoxybenzyl)-6-(1 -(((1 R,3S)-3-aminocyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine 4-carboxamide (prepared as described in Example 137) (39 mg, 0.089 mmol), triethylamine (35 pL, 0.25 mmol, 2.80 equiv.), 2-acetoxyacetyl chloride (20 pL, 0.19 mmol, 2.10 equiv.), and 2.0 N aqueous lithium hydroxide (0.45 mL, 0.89 mmol, 10.0 equiv.). Purification by silica gel chromatography 30 (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (25 mg, 56%). MS (ES+) m/z 498 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.39 (1 H, t, J=6.2 Hz), 8.89 (1 234 WO 2009/016498 PCT/IB2008/002046 H, s), 8.34 (1 H, s), 7.61 (1 H, d, J=7.5 Hz), 7.18 (1 H, dd, J=8.6, 1.5 Hz), 7.14 (1 H, dd, J=11.6, 8.3 Hz), 6.82 - 6.96 (1 H, m), 5.31 (1 H, t, J=5.9 Hz), 4.50 (2 H, d, J=6.4 Hz), 4.46 (2 H, dd, J=7.0, 2.1 Hz), 4.02 - 4.16 (1 H, m), 3.82 (3 H, s), 3.77 (2 H, d, J=5.9 Hz), 2.75 (3 H, s), 1.90 - 2.01 (1 H, m), 1.75 1.90 (1 H, m), 1.42 - 1.70 (4 H, m), 1.21 - 1.35 (1 H, m). 5 Example 140 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1-(((1R,3S)-3 (methylsulfonamido)cyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)pyrimidine-4-carboxamide F 0 HN HN-S -0 N/:- N I I - N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-(1-(((S)-4 10 acetylmorpholin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (Example 131) by reaction of the hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((1R,3S)-3 aminocyclopentyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 137) (39 mg, 0.089 mmol), triethylamine (35 pL, 0.25 mmol, 2.80 equiv.), and methanesulfonyl chloride (15 pL, 0.19 mmol, 2.10 equiv.). Purification by silica gel chromatography 15 (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (33 mg, 72%). MS (ES+) m/z 518 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 9.39 (1 H, t, J=6.5 Hz), 8.89 (1 H, s), 8.34 (1 H, s), 7.18 (1 H, dd, J=8.6, 1.6 Hz), 7.11 - 7.17 (1 H, m), 7.09 (1 H, d, J=7.3 Hz), 6.83 6.96 (1 H, m), 4.50 (2 H, d, J=6.2 Hz), 4.45 (2 H, d, J=7.3 Hz), 3.82 (3 H, s), 3.51 - 3.71 (1 H, m), 2.88 (3 H, s), 2.75 (3 H, s), 1.97 - 2.09 (1 H, m), 1.82 - 1.96 (1 H, m), 1.35 - 1.72 (4 H, m), 1.19 - 1.34 (1 H, 20 m). Example 141 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-aminocyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide F N H2 -O N.:,N N N - o N - N N "N N H 25 Step 1: Preparation of ((1 S,3R)-3-(tert-butoxycarbonyl)cyclopentyl)methy methanesulfonate. 00 9 ,O H ,-sO0 0 , N O,0, 0 tert-Butyl (1 R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (prepared from commercially available 1-(S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one according to the method described by Shuto 235 WO 2009/016498 PCT/IB2008/002046 and coworkers, see Kudoh, T. et al. J. Am. Chem. Soc. 2005, 127, 8846-8855) (250 mg, 1.16 mmol), methanesulfonyl chloride (108 pL, 1.39 mmol, 1.20 equiv.), and N,N-diisopropylethylamine (263 pL, 1.51 mmol, 1.30 equiv.) were combined in dichloromethane (5.0 mL). After stirring for 30 minutes at 0 *C, the mixture was diluted with dichloromethane (15 mL) and 10% aqueous sodium bisulfate (5 mL). 5 The layers were separated and the aqueous layer was washed with dichloromethane (3 x 2 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (341 mg, >95%). Step 2: Preparation of tert-butyl (1 R,3S)-3-(azidomethyl )cyclopentylcarbamate. H N '',.N 0 N3 0 , r0, 0 10 ((1S,3R)-3-(tert-Butoxycarbonyl)cyclopentyl)methyl methanesulfonate (100 mg, 0.34 mmol) and sodium azide (69 mg, 1.07 mmol, 3.15 equiv.) were combined in N,N-dimethylformamide (0.60 mL). After stirring for 15 hours at 50 *C, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (3 x 2 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography 15 (gradient 4:1 heptane/EtOAc to 2:1 heptane/EtOAc) provided the crude title compound as a pale orange oil (82 mg, >95%) that was used in subsequent reactions without further purification. Step 3: Preparation of terd-butyl (1R,3S)-3-((4-(6-((4-fluoro-3-methoxybenzvl)carbamoyl)-2 methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-vl)methyl)cyclopentvlcarbamate. F 5N 0 0 / \ N 0 N 20 The title compound was prepared in a similar manner to ter-butyl (1S,3R)-3-((4-(6-((4-fluoro 3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)- 1 H- 1,2,3-triazol- 1 yl)methyl)cyclopentylcarbamate (step 3, Example 137) by the reaction of tert-butyl (1R,3S)-3 (azidomethyl)cyclopentylcarbamate (82 mg, 0.34 mmol), N-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2 methylpyrimidine-4-carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3 25 methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2 methylpyrimidine-4-carboxamide, Example 128) (102 mg, 0.34 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (34 pL, 0.034 mmol, 0.10 equiv.), and 0.30 M aqueous copper (II) sulfate (23 pL, 0.007 mmol, 0.02 equiv.) to afford title compound as a light yellow foam (128 mg, 70%). LC/MS (5% 100% CH 3
CN/H
2 0, 5 min): 3.78 min, m/z 484 (M - 2-Me-propene + H). 236 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of N-(4-fluoro-3-methoxybenzvl)-6-(1 -(((1 S,3R)-3-aminocyclopentyl)methyl)- 1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide. F N O NH2 HN N N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-6-(1 5 (((1R,3S)-3-aminocyclopentyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (step 4, Example 137) by the reaction of tert-butyl (1 R,3S)-3-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)cyclopentylcarbamate (128 mg, 0.24 mmol) and 4.0 N hydrochloric acid in methanol (1.5 mL, 6.00 mmol, 25.Oequiv.) to afford the hydrochloride salt form of title compound as a white solid (114 mg, >95%) that was used in subsequent reactions without 10 further purification. LC/MS (5%-100% CH 3
CN/H
2 0, 5 min): 2.73 min, m/z 440 (M+H). Example 142 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-acetamidocyclopentyl)methyl)-1 H-1,2,3-triazol-4 yl)-2-methylpyrimidine-4-carboxamide F HN O HN O -O NzN N N 15 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-(1-(((S)-4 acetylmorpholin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (Example 131) by reaction of the hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((1S,3R)-3 aminocyclopentyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 141) (38 mg, 0.079 mmol), triethylamine (35 pL, 0.25 mmol, 3.16 equiv.), and 20 acetyl chloride (11 pL, 0.16 mmol, 2.02 equiv.). Purification by reverse phase HPLC provided the title compound as a white solid (15 mg, 39%). MS (ES+) m/z 482 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 9.39 (1 H, t, J=6.2 Hz), 8.89 (1 H, s), 8.34 (1 H, s), 7.81 (1 H, d, J=7.0 Hz), 7.18 (1 H, dd, J=8.5, 1.6 Hz), 7.14 (1 H, dd, J=11.6, 8.3 Hz), 6.84 - 6.95 (1 H, m), 4.50 (2 H, d, J=6.4 Hz), 4.45 (2 H, d, J=7.1 Hz), 3.91 - 4.05 (1 H, m), 3.82 (3 H, s), 2.75 (3 H, s), 1.90 - 2.02 (1 H, m), 1.78 - 1.88 (1 H, m), 1.76 (3 25 H, s), 1.57 - 1.70 (1 H, m), 1.37 - 1.53 (2 H, m), 1.09 - 1.21 (1 H, m). Example 143 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-(2-hydroxyacetamido)cyclopentyl)methyl)-1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide 237 WO 2009/016498 PCT/IB2008/002046 F N O HN -0 H N'N \ OH N N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-6-(1 (((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4 carboxamide (Example 136) by reaction of the hydrochloride salt form of N-(4-fluoro-3 5 methoxybenzyl)-6-(1 -(((1 S,3R)-3-aminocyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine 4-carboxamide (prepared as described in Example 141) (38 mg, 0.079 mmol), triethylamine (35 ,uL, 0.25 mmol, 3.16 equiv.), 2-acetoxyacetyl chloride (17 pL, 0.16 mmol, 2.02 equiv.), and 2.0 N aqueous lithium hydroxide (0.40 mL, 0.80 mmol, 10.1 equiv.). Purification by reverse phase HPLC provided the title compound as a white solid (16 mg, 41%). MS (ES+) m/z 498 (M+H). 1 H NMR (400 MHz, DMSO 10 d 6 ) 6 9.39 (1 H, t, J=6.4 Hz), 8.89 (1 H, s), 8.34 (1 H, s), 7.61 (1 H, d, J=7.7 Hz), 7.18 (1 H, dd, J=8.5, 1.9 Hz), 7.14 (1 H, dd, J=1 1.6, 8.3 Hz), 6.87 - 6.96 (1 H, m), 5.32 (1 H, t, J=5.7 Hz), 4.50 (2 H, d, J=6.2 Hz), 4.39 - 4.48 (2 H, m), 4.04 - 4.16 (1 H, m), 3.82 (3 H, s), 3.77 (2 H, d, J=5.9 Hz), 2.75 (3 H, s), 1.90 - 2.03 (1 H, m), 1.77 - 1.90 (1 H, m), 1.41 - 1.70 (4 H, m), 1.21 - 1.35 (1 H, m). Example 144 15 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 -(((1 S,3R)-3 (methylsulfonamido)cyclopentyl)methyl)-1 H-1,2,3-triazol-4-yl)pyrimidine-4-carboxamide F O HN HN-S -O N N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-(1-(((S)-4 acetylmorpholin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (Example 131) 20 by reaction of the hydrochloride salt form of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((1S,3R)-3 aminocyclopentyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 141) (38 mg, 0.079 mmol), triethylamine (35 pL, 0.25 mmol, 3.16 equiv.), and methanesulfonyl chloride (12 pL, 0.16 mmol, 2.02 equiv.). Purification by reverse phase HPLC provided the title compound as a white solid (12 mg, 29%). MS (ES+) m/z 518 (M+H). 1H NMR (400 25 MHz, DMSO-d 6 ) d 9.38 (1 H, t, J=6.3 Hz), 8.89 (1 H, s), 8.33 (1 H, s), 7.18 (1 H, dd, J=8.4, 1.8 Hz), 7.13 (1 H, dd, J=1 1.7, 8.4 Hz), 7.09 (1 H, d, J=7.1 Hz), 6.86 - 6.95 (1 H, m), 4.49 (2 H, d, J=6.2 Hz), 4.45 (2 H, d, J=7.3 Hz), 3.82 (3 H, s), 3.56 - 3.70 (1 H, m), 2.87 (3 H, s), 2.74 (3 H, s), 1.97 - 2.09 (1 H, m), 1.83 - 1.95 (1 H, m), 1.39 - 1.69 (3 H, m), 1.20 - 1.33 (1 H, m). Example 145 30 6-(1-(((S)-1,4-Dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(4-fluoro-3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide 238 WO 2009/016498 PCT/IB2008/002046 F 0 -OH N 0 N N N", O Step 1: Preparation of (R)-(1,4-dioxan-2-yl)methyl trifluoromethanesulfonate. 0 0
F
3 C 0~ 0 The title compound was prepared in a similar manner to ((2S,5R)-5 5 ((trifluoromethylsulfonyloxy)methyl)-1,4-dioxan-2-yl)methy 4-methylbenzenesulfonate (step 5, Example 128) by reaction of (S)-(1,4-dioxan-2-yl)methanol (prepared as described in step 1 of the synthesis of 6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide, Example 57) (100 mg, 0.85 mmol), pyridine (72 pL, 0.89 mmol, 1.05 equiv.), and trifluoromethanesulfonic anhydride (150 pL, 0.89 mmol, 1.05 equiv.) to afford the title 10 compound as a tan oil (185 mg, 87%). 1 H NMR (400 MHz, CDCl 3 ) 6 4.40 - 4.54 (2 H, m), 3.90 - 3.97 (1 H, m), 3.72 - 3.90 (4 H, m), 3.59 - 3.70 (1 H, m), 3.48 (1 H, dd, J=11.4, 10.0 Hz). Step 2: Preparation of 6-(1-(((S)-1,4-dioxan-2-Vl)methyl)-1H-1,2,3-triazol-4-yi)-N-(4-fluoro-3 methoxybenzyl)-2-methylpyrimidine-4-carboxamide. -0 N \ N 0 N N "0O 15 The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (R)-(1,4-dioxan-2-yl)methyl trifluoromethanesulfonate (175 mg, 0.70 mmol, 1.20 equiv.), sodium azide (38 mg, 0.58 mmol, 1.00 equiv.), N-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4-carboxamide (prepared as 20 described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (174 mg, 0.58 mmol), 1.0 M aqueous sodium ascorbate (58 pL, 0.058 mmol, 0.10 equiv.), and 0.30 M aqueous copper (11) sulfate (40 pL, 0.012 mmol, 0.02 equiv.). Purification by silica gel chromatography (gradient 1:2 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (258 mg, 25 >95%). MS (ES+) m/z 443 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 9.47 (1 H, t, J=6.4 Hz), 8.82 (1 H, s), 8.33 (1 H, s), 7.10 - 7.24 (2 H, m), 6.90 (1 H, ddd, J=8.1, 4.3, 1.8 Hz), 4.50 - 4.65 (2 H, m), 4.49 (2 H, d, J=6.8 Hz), 3.94 - 4.06 (1 H, m), 3.80 - 3.87 (4 H, m), 3.75 (1 H, d, J=11.3 Hz), 3.64 (1 H, d, J=1 1.0 Hz), 3.51 - 3.59 (1 H, m), 3.40 - 3.50 (1 H, m), 3.24 - 3.33 (1 H, m), 2.75 (3 H, s). 239 WO 2009/016498 PCT/IB2008/002046 Example 146 6-(1-(((R)-1,4-Dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(4-fluoro-3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide F 0 -O _ N 0 N 0 NNO 5 Step 1: Preparation of (S)-(1,4-dioxan-2-yl)methyl trifluoromethanesulfonate. 0 0 F3C'' O The title compound was prepared in a similar manner to ((2S,5R)-5 ((trifluoromethylsulfonyloxy)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 5, Example 128) by reaction of (R)-(1,4-dioxan-2-yl)methanol (prepared as described in step 1 of the 10 synthesis of 6-(2-(((R)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-2 methylpyrimidine-4-carboxamide, Example 53) (54 mg, 0.46 mmol), pyridine (41 pL, 0.50 mmol, 1.10 equiv.), and trifluoromethanesulfonic anhydride (85 pL, 0.50 mmol, 1.10 equiv.) to afford the title compound as a tan oil (96 mg, 84%). Step 2: Preparation of 6-(1 -(((R)- 1,4-dioxan-2-yl)methyl)- 1 H-1,2,3-triazol-4-yl)-N-(4-fluoro-3 15 methoxybenzyl)-2-methylpyrimidine-4-carboxamide. F N HN -o N N O The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1 H-1,2,3-triazol-1 -yl)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (S)-(1,4-dioxan-2-yl)methyl 20 trifluoromethanesulfonate (96 mg, 0.38 mmol, 1.30 equiv.), sodium azide (20 mg, 0.31 mmol, 1.05 equiv.), N-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4-carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-( 1-(((2S, 5R)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (88 mg, 0.30 mmol), 1.0 M aqueous sodium ascorbate (30 pL, 0.030 mmol, 0.10 equiv.), and 0.30 M 25 aqueous copper (II) sulfate (20 pL, 0.006 mmol, 0.02 equiv.). Purification by silica gel chromatography (gradient 1:2 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (95 mg, 73%). MS (ES+) m/z 443 (M+H). 'H NMR (400 MHz, DMSO-d) 6 9.47 (1 H, t, J=6.2 Hz), 8.82 (1 H, s), 8.33 (1 H, s), 7.11 - 7.22 (2 H, m), 6.85 - 6.94 (1 H, m), 4.51 - 4.63 (2 H, m), 4.49 (2 H, d, J=6.6 240 WO 2009/016498 PCT/IB2008/002046 Hz), 3.96 - 4.05 (1 H, m), 3.79 - 3.87 (4 H, m), 3.75 (1 H, d, J=1 1.5 Hz), 3.64 (1 H, d, J=1 1.2 Hz), 3.51 - 3.59 (1 H, m), 3.41 - 3.49 (1 H, m), 3.25 - 3.32 (1 H, m), 2.75 (3 H, s). Example 147 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-amino-tetrahydro-2H-pyran-2-yl)methyl)-1 H-1,2,3 5 triazol-4-yI)-2-methylpyrimidine-4-carboxamide F N -O N N O -NH2 N Step 1: Preparation of ((2S,5R)-5-(tert-butoxycarbonyl)-tetrahydro-2H-pyran-2-yl)methyl 2,2,2 trifluoroethanesulfonate. 0 0
F
3 C ,S 'O O N O H 10 ter-Butyl (3R,6S)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-ylcarbamate (prepared from commercially available tri-O-acetyl-D-glucal according to the method described by Overkleeft and coworkers, see Kriek, N. M. A. J. et al. Eur. J. Org. Chem. 2003, 2418-2427) (75 mg, 0.32 mmol), 2,2,2-trifluoroethanesulfonyl chloride (43 pL, 0.39 mmol, 1.20 equiv.), and triethylamine (59 pL, 0.42 mmol, 1.30 equiv.) were combined in dichloromethane (2.0 mL). After stirring for 2 hours at 0 *C, the 15 mixture was diluted with dichloromethane (10 mL) and 10% aqueous sodium bisulfate (3 mL). The layers were separated and the aqueous layer was washed with dichloromethane (3 x 1 mL), The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a faint yellow residue. Purification by silica gel chromatography (gradient 2:1 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (111 mg, 91%). 1 H NMR (400 MHz, 20 CDC13) 6 4.33 (2 H, d, J=4.8 Hz), 4.27 (1 H, br. s.), 3.88 - 4.19 (3 H, m), 3.48 - 3.70 (2 H, m), 3.03 (1 H, t, J=10.8 Hz), 2.06 - 2.25 (1 H, m), 1.65 - 1.79 (1 H, m), 1.46 - 1.58 (1 H, m), 1.45 (9 H, s), 1.24 1.40 (1 H, m). Step 2: Preparation of terd-butyl (3R,6S)-6-((4-(6-((4-fluoro-3-methoxvbenzvl)carbamoyl)-2 methylpyrimidin-4-yl)-1 H-1,23-triazol-1 -yl)methyl)-tetrahydro-2H-pyran-3-ylcarbamate. F 0 -0 N H N N O N ~0/ 25 ((2S,5R)-5-(ted-Butoxycarbonyl)-tetrahydro-2H-pyran-2-yl)methyl 2,2,2 trifluoroethanesulfonate (97 mg, 0.26 mmol) and sodium azide (18 mg, 0,28 mmol, 1.10 equiv.) were combined in N,N-dimethylformamide (0.50 mL). After stirring for 18 hours at room temperature, the 241 WO 2009/016498 PCT/IB2008/002046 reaction vessel was charged sequentially with N,N-dimethylformamide (1.0 mL), water (0.50 mL), N (4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4-carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-(hydroxymethyl)- 1, 4-dioxan 2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (77 mg, 0.26 5 mmol, 1.00 equiv.), 1.0 M aqueous sodium ascorbate (26 pL, 0.026 mmol, 0.10 equiv.), and 0.30 M aqueous copper (11) sulfate (17 pL, 0.005 mmol, 0.02 equiv.). After stirring for 15 hours at room temperature, water (15 mL) was added, the precipitate was collected by suction filtration, and the filter cake was washed with water (3x). The solid was dissolved in ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. Purification by silica gel 10 chromatography (gradient 1:1 heptane/EtOAc to 100% EtOAc) provided the title compound as a pale yellow solid (95 mg, 66%). LC/MS (5%-100% CH 3
CN:H
2 0, 5 min): 3.61 min, m/z 556 (M+H). Step 3: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-amino-tetrahydro-2H-pyran-2 yl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide F N -O N N O NH2 N -N 15 tert-Butyl (3R,6S)-6-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1H 1,2,3-triazol-1-yl)methyl)-tetrahydro-2H-pyran-3-ylcarbamate (95 mg, 0.17 mmol) was dissolved in 4.0 N hydrochloric acid in 1,4-dioxane (1.0 mL, 4.00 mmol, 23.5 equiv.). After stirring for 2 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol, concentrated under reduced pressure, and dried under high vacuum to afford the title 20 compound as the hydrochloride salt (84 mg, >95%) Example 148 N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-acetamido-tetrahydro-2H-pyran-2-yl)methyl)-1 H 1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide F HN 0 -O N NN 0 H N Nr 25 The hydrochloride salt of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-amino-tetrahydro-2H pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide (prepared as described in Example 147) (84 mg), triethylamine (71 pL, 0.51 mmol, 3.00 equiv.), and acetyl chloride (24 pL, 0.34 mmol, 2.00 equiv.) were combined in dichloromethane (1.2 mL). After stirring for 15 hours at room temperature, methanol (2 mL) was added and the mixture concentrated under reduced pressure to 30 give a salty residue. Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (60 mg, 71%). MS (ES+) m/z 498 (M+H). 242 WO 2009/016498 PCT/IB2008/002046 'H NMR (400 MHz, DMSO-d,) 6 9.47 (1 H, t, J=6.3 Hz), 8.77 (1 H, s), 8.33 (1 H, s), 7.74 (1 H, d, J=7.7 Hz), 7.08 - 7.24 (2 H, m), 6.82 - 6.96 (1 H, m), 4.55 - 4.64 (1 H, m), 4.43 - 4.54 (3 H, m), 3.70 - 3.86 (5 H, m), 3.52 - 3.67 (1 H, m), 2.92 (1 H, t, J=10.6 Hz), 2.75 (3 H, s), 1.83 - 1.95 (1 H, m), 1.68 - 1.82 (4 H, m), 1.20 - 1.50 (2 H, m). 5 Example 149 N-(4-Fluoro-3-methoxybenzyl)-6-(5-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1,2,4 oxadiazol-3-yI)-2-methylpyrimidine-4-carboxamide F N O -Q HN -O NO N N ' O H Step 1:Preparation of ((2S,5S)-5-(cyanomethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 0 0O N O 10 Potassium cyanide (580 mg, 8.91 mmol) was added to a solution of ((2S,5R)-5 ((trifluoromethylsulfonyloxy)methyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 5 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide, Example 128) (3.87 15 g, 8.91 mmol) in acetonitrile (30 mL) and water (3 ml). The mixture was stirred for 2 hours at room temperature and then was concentrated. The residue washed with water and dried to afford the title compound as a solid (2.17 g, 78%). Step 2: Preparation of ((2S,5S)-5-(2-oxoethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate 0 \\0 0 0"- O H/ O 20 A diisobutylaluminum hydride solution (1 M in dichloromethane, 17.4 mL, 17.4 mmol) was added to a solution of ((2S,5S)-5-(cyanomethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (2.17 g, 6.97 mmol) in dichloromethane (60 mL) cooled in a dry ice/acetone bath. The mixture was stirred at -78 *C for 1 hour. 1 N Hydrochloric acid solution (25 mL) was added and the mixture was allowed to warm to room temperature. The mixture was poured into water (100 mL) and extracted with 25 ethyl acetate (3x). The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (553 mg, 25%). 1 H NMR (400 MHz, CDCl 3 ) 6 ppm 2.32 - 2.42 (m, 1 H), 2.44 (s, 3 H), 2.47 - 2.58 (m, 1 H), 3.25 243 WO 2009/016498 PCT/IB2008/002046 - 3.48 (m, 2 H), 3.67 - 3.83 (m, 3 H), 3.89 - 4.03 (m, 3 H), 7.34 (d, J=8.01 Hz, 2 H), 7.77 (d, J=8.40 Hz, 2 H), 9.57 - 9.80 (m, 1 H). Step 3: Preparation of ((2S, 5S)-5-((((4-methylphenvl)sulfonvl)oxv)methvl)- 1 ,4-dioxan-2-yl)acetic acid 0 \\ HO~K' 5 ((2S,5S)-5-(2-oxoethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (390 mg, 1.24 mmol) was dissolved in t-butanol (20 mL). A 2M solution of 2-methyl-2-butene (12.4 mL, 24.8 mmol) was added to the stirring mixture followed by a solution of sodium chlorite (1.12 g, 10 mmol) and mono-sodium phosphate (monobasic) monohydrate (2.23 g, 13.0 mmol) in water (10 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane 10 and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with dichloromethane (3x). The combined organic layers were dried over magnesium sulfate and concentrated to afford the title compound as an oil which crystallized upon standing (515 mg). MS (ES+) m/z 331 (M+H). Step 5: Preparation of ((2S,5S)-5-(2-(((6-(((4-fluoro-3-methoxvbenzvl)amino)carbonyl)-2 15 methylpyrimidin-4-vl)(hydroxvimino)methyl)amino)-2-oxoethyl)-1,4-dioxan-2-vl)methyl 4 methylbenzenesulfonate 0 -0 0 HO'N O O H0N N O FNsN A mixture of N-(4-fluoro-3-methoxybenzyl)-6-(carbamimidoyl)-2-methylpyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(5 20 ((trans-4-aminocyclohexyl)methyl)-1,2,4-oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 122) (353 mg, 1.06 mmol), ((2S,5S)-5-((((4-methylphenyl)sulfonyl)oxy)methyl)-1,4-dioxan-2-yl)acetic acid (350 mg, 1.06 mmol), 1-hydroxybenzotriazole ( 143 mg, 1.06 mmol), diisopropylethylamine (0.55 mL, 3.18 mmol), and polymer supported-carbodiimide resin (2.86 g, 3.18 mmol) in acetonitrile (10 mL) was stirred at 40 *C for 42 hours. The reaction mixture was filtered and the resin was washed with 25 acetonitrile. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (155 mg, 23%). 244 WO 2009/016498 PCT/IB2008/002046 Step 6: Preparation of N-(4-fluoro-3-methoxybenzvl)-6-(5-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2 yl )methyl)- 1 ,2,4-oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide F N -Q HN -O N N Z\ 'O O - OH N N O A solution of ((2S,5S)-5-(2-(((6-(((4-fluoro-3-methoxybenzyl)amino)carbonyl)-2 5 methylpyrimidin-4-yl)(hydroxyimino)methyl)amino)-2-oxoethyl)-1,4-dioxan-2-yl)methyl 4 methylbenzenesulfonate (134 mg, 0.209 mmol) in acetonitrile (5 mL) was treated with MP-carbonate resin and heated to 65 OC for 18 hours. The resin was filtered and washed with acetonitrile. The filtrate was concentrated to a volume of 5 mL. Tetrabutyl ammonium acetate (126 mg, 0.418 mmol) was added and the mixture was heated to 65 *C for 5 hours. The mixture was then treated with a 2.5 M 10 sodium hydroxide solution (1 mL) and the solution was stirred at room temperature for 18 hours. After reaction mixture was purified by reverse phase preparative HPLC. The crude product was dissolved in ethyl acetate and washed several times with a saturated solution of ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as an oil (22 mg, 11%). MS (ES+) m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.25 (d, J=5.49 Hz, 2 H), 15 2.83 (s, 3 H), 3.07 - 3.22 (m, 2 H), 3.31 - 3.54 (m, 4 H), 3.74 - 3.87 (m, 4 H), 4.50 (d, J=6.22 Hz, 2 H), 4.60 - 4.72 (m, 1 H), 5.28 (dd, 1 H), 6.80 - 6.98 (m, 1 H), 7.06 - 7.25 (m, 2 H), 8.33 (s, 1 H), 9.43 - 9.60 (m, 1 H). Example 150 6-(5-((2R)-1,4-Dioxan-2-ylmethyl)-1,2,4-oxadiazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2 20 methylpyrimidine-4-carboxamide F-P HN 0 SN 0 Step 1: Preparation of (2R)-1,4-dioxan-2-ylacetonitrile O Potassium cyanide (2.27 g) was added to (S)-(1,4-dioxan-2-yl)methyl 25 trifluoromethanesulfonate (prepared as describe in step 1 of the synthesis of 6-(1-(((R)-1,4-dioxan-2 yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide, Example 146) (7.3 g, 29.0 mmol) in a mixture of acetonitrile (60 mL) and water (6 mL). The mixture was stirred at room temperature for 18 hours and was then concentrated. The residue was taken up 245 WO 2009/016498 PCT/IB2008/002046 in ethyl acetate and washed with water (2x). The organic layer was dried over sodium sulfate to afford the title compound as an oil (3.23 g, 87%). MS (ES+) m/z 128 (M+H). Step 2: Preparation of methyl (2R)-1,4-dioxan-2-ylacetate 00 0 5 (2R)-1,4-dioxan-2-ylacetonitrile (3.2 g, 25.0 mmol) was dissolved in methanol (10 mL) and HCI gas was bubbled through the mixture for several minutes. The resulting solution was stirred at room temperature for 1 hour. Water (2 mL) was added and most of the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, and concentrated to afford the title compound as an 10 oil. MS (ES+) m/z 161 (M+H). Step 3: Preparation of (2R)-1,4-dioxan-2-ylacetic acid HO O O O' A mixture of methyl (2R)-1,4-dioxan-2-ylacetate (300 mg, 1.87 mmol), tetrahydrofuran (5 mL), water (1 mL), and lithium hydroxide (359 mg, 15.0 mmol) was stirred at room temperature for 18 15 hours. The mixture was acidified with the addition of 3N hydrochloric acid and then passed through a Chem Elute extraction column eluting with ethyl acetate. The eluant was concentrated to afford the title compound as a solid (262 mg, 96%). MS (ES+) m/z 147 (M+H). Step 4: Preparation of 6-(5-((2R)-1,4-dioxan-2-vlmethyl)-1,2,4-oxadiazol-3-yl)-N-(4-fluoro-3 methoxybenzvl)-2-methylpyrimidine-4-carboxamide F N -O N- 0 N 0 N N N 0 20 A mixture of N-(4-fluoro-3-methoxybenzyl)-6-(carbamimidoyl)-2-methylpyrimidine-4 carboxamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(5 ((trans-4-aminocyclohexyl)methyl)-1,2,4-oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 122) (100 mg, 0.30 mmol), (2R)-1,4-dioxan-2-ylmethanol (87 mg, 0.60 mmol), 1-hydroxybenzotriazole 25 (61 mg, 0.45 mmol), polymer supported-carbodiimide resin (811 mg, 0.90 mmol), and diisopropylamine (0.16 mL, 0.90 mmol) in acetonitrile (5 mL) was heated to 40 0C for 3 days. The reaction mixture was filtered and the resin was washed with a minimal amount of acetonitrile. The filtrate was then treated with MP-carbonate resin (523 mg, 1.5 mmol) and heated to 65 *C for 18 hours. The mixture was filtered and the resin was washed with acetonitrile. The filtrate was 30 concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (16 mg, 12%). MS (ES+) m/z 444 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.82 (s, 3 H), 3.13 - 3.20 (m, 1 H), 3.22 - 3.31 (m, 2 H), 3.42 - 3.50 (m, 1 H), 3.54 - 3.66 (m, 2 H), 3.68 246 WO 2009/016498 PCT/IB2008/002046 - 3.73 (m, 1 H), 3.77 - 3.89 (m, 4 H), 4.00 - 4.08 (m, 1 H), 4.48 (d, J=6.22 Hz, 2 H), 6.88 (ddd, J=8.33, 4.30, 2.01 Hz, 1 H), 7.09 - 7.19 (m, 2 H), 8.32 (s, 1 H), 9.55 - 9.62 (m, 1 H). Example 151 6-(5-((2S)-1,4-Dioxan-2-ylmethyl)-1,2,4-oxadiazol-3-yI)-N-(4-fluoro-3-methoxybenzyl)-2 5 methylpyrimidine-4-carboxamide F N - HN N N N 0 0 The title compound was prepared in a similar manner to 6-(5-((2R)-1,4-dioxan-2-ylmethyl) 1,2,4-oxadiazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (Example 150) starting from (S)-1,4-dioxan-2-ylmethanol (prepared as described in step 1 of the synthesis of 6-(2 10 (((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol5-yl)-N-(3-methyoxybenzyl)-2-methylpyrimidine-4 carboxamide, Example 57) to afford 75 mg (56%). MS (ES+) m/z 444 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 2.82 (s, 3 H), 3.12 - 3.21 (m, 1 H), 3.22 - 3.30 (m, 1 H), 3.42 - 3.50 (m, 1 H), 3.55 (d, J=2.56 Hz, 1 H), 3.57 - 3.66 (m, 2 H), 3.68 - 3.73 (m, 1 H), 3.77 - 3.90 (m, 4 H), 4.00 - 4.08 (m, 1 H), 4.48 (d, J=6.22 Hz, 2 H), 6.88 (ddd, J=8.33, 4.30, 2.01 Hz, 1 H), 7.09 - 7.19 (m, 2 H), 8.32 (s, 1 H), 15 9.55 - 9.62 (m, 1 H). Example 152 N-(4-Fluoro-3-methoxybenzyl)-6-(3-(((trans)-4-acetamidocyclohexyl)methyl)isoxazo-5-yl)-2 methylpyrimidine-4-carboxamide F 0 -P HN -0N 0 ON 20 Step 1: Preparation of tert-butyl (trans)-4-((E)-2-(hydroxyimino)ethyl)cyclohexylcarbamate HO'N HH NO< H tert-Butyl (trans)-4-(2-oxoethyl)cyclohexylcarbamate (403 mg, 1.67 mmol) was dissolved in a mixture of ethanol (12 ml) and water (8 mL). Sodium acetate (407 mg, 4.96 mmol) was added and the mixture was stirred for 30 min at room temperature. Hydroxylamine hydrochloride (363 mg, 5.01 25 mmol) was added and the mixture was heated to 60 *C for 1.5 hours. The reaction mixture was concentrated to obtain the title compound as a white solid (70 mg). 247 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of tert-butyl (trans)-4-((Z)-2-chloro-2-(hydroxyimino)ethyl)cyclohexylcarbamate N, HO'N 0 N O H N-Chlorosuccinimide (51.5 mg, 0.38 mmol) was added to a solution of tert-butyl (trans)-4-((E) 2-(hydroxyimino)ethyl)cyclohexylcarbamate (99 mg, 0.38 mmol) in acetonitrile( 5 mL) and the mixture 5 was stirred at room temperature for 18 hours. Additional N-chlorosuccinimide was added (25.7 mg, 0.19 mmol). After 4 hours, the reaction mixture was concentrated. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated to afford the title compound as a white solid (177 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.621 min., m/z 338 (M+H). 1 H NMR (400 MHz, CDCl 3 ) 6 ppm 1.09 (d, J=10.16 Hz, 2 H), 1.43 (s, 9 H), 1.77 (d, J=10.94 Hz, 2 H), 2.77 (s, 5 H), 10 2.92 (s, 1 H), 5.30 (s, 1 H). Step 3: Preparation of tert-butyl (trans)-4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)isoxazol-3-vl)methyl)cyclohexylcarbamate F 0 O -P HN -O O H N NN tert-Butyl (trans)-4-((Z)-2-chloro-2-(hydroxyimino)ethyl)cyclohexylcarbamate (48.6 mg, 0.16 15 mmol) was added to a mixture of N-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrimidine-4 carboxamide (prepared as described in step 4 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(1 (((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,3-triazol-4-yl)-2-methylpyrimidine-4 carboxamide, Example 128) (50.1 mg, 0.16 mmol) and triethylamine (0.023 mL, 0.16 mmol) in toluene (5 mL). The mixture was stirred at room temperature for 2 hours, then heated to 110 *C for 2 hours, 20 and finally allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as an orange solid (51.7 mg, 46%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.72 min., m/z 498 (M-C 4 H). IH NMR (400 MHz, CDCl 3 ) 6 ppm 1.02 - 1.20 (m, 4 H), 1.22 - 1.27 (m, 1 H), 1.36 - 1.51 (m, 9 H), 1.58 1.72 (m, 1 H), 1.80 (d, J=10.55 Hz, 2 H), 1.94 - 2.06 (m, 2 H), 2.64 (d, J=7.04 Hz, 2 H), 2.74 - 2.82 (m, 25 3 H), 3.36 (br. s., 1 H), 3.84 - 3.91 (m, 3 H), 4.62 (d, J=5.86 Hz, 2 H), 5.28 (s, 1 H), 6.83 - 6.91 (m, 1 H), 6.92 - 6.99 (m, 2 H), 6.99 - 7.07 (m, 1 H), 8.29 - 8.37 (m, 1 H), 8.38 (s, 1 H). 248 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of N-(4-fluoro-3-methoxvbenzyl)-6-(3-(((trans)-4 acetamidocyclohexyl)methyl)isoxazol-5-yl)-2-methylpyrimidine-4-carboxamide F N' \ O -P HN -O N O'N N N 0 Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (trans)-4-((5-(6-((4-fluoro-3 5 methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)isoxazol-3-yl)methyl)cyclohexylcarbamate (51 mg, 0.076 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and the residue was dissolved in N,N-dimethylformamide (10 mL). Diisopropylethylamine (0.05 mL, 0.30 mmol) and acetic anhydride (0.015 mL, 0.152 mmol) were added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction 10 mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (32.3 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.062 min., m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.03 - 1.15 (m, 4 H), 1.17 (d, J=0.73 Hz, 1 H), 1.69 (d, J=1 1.71 Hz, 3 H), 1.73 - 1.79 (m, 5 H), 2.61 (d, J=6.95 Hz, 2 H), 2.79 (s, 3 H), 3.31 (br. s., 1 H), 3.44 (dt, J=7.05, 3.61 Hz, 1 H), 3.81 (s, 3 H), 4.48 (d, J=6.59 Hz, 2 H), 6.89 (ddd, J=8.33, 4.30, 2.01 15 Hz, 1 H), 7.09 - 7.20 (m, 2 H), 7.41 (s, 1 H), 7.71 (d, J=7.69 Hz, 1 H), 8.20 (s, 1 H), 9.50 - 9.57 (m, 1 H). Example 153 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide O H N N
NH
2 o N 20 Step 1: Preparation of N-tert-butyl-2-chloro-6-methylisonicotinamide Cl H N N- - 0 Oxalyl chloride (95 mL, 1.10 mol) was added to 2-chloro-6-methylisonicotinic acid (95 g, 0.55 mol) in dichloromethane (950 mL, anhydrous) The mixture was cooled in an ice/water bath and DMF 25 (2.0 mL) was slowly added. When gas evolution subsided, the ice/water bath was removed and the mixture was allowed to reach ambient temp and stir for 15 hours. The solution was then concentrated in vacuo and azeotroped with toluene (2 x 200 mL). The residue was taken into dichloromethane (800 mL, anhydrous), cooled in an ice/water bath, and a solution of tert-butylamine (175 mL, 1.7 mol) in 249 WO 2009/016498 PCT/IB2008/002046 dichloromethane (300 mL, anhydrous) was added drop wise. The mixture was allowed to reach ambient temp and stir for 15 hours. Water (250 mL) was added. The organic layer was washed with water (200 mL) followed by brine (200 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a beige solid (120 g, 96%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.39 5 (s, 1 H), 7.38 (s, 1 H), 6.05 (s, 1 H), 2.59 (s, 3 H), 1.5 (s, 9 H). Step 2: Preparation of 2-chloro-6-methylisonicotinonitrile Cl N CN To N-tert-butyl-2-chloro-6-methylisonicotinamide (120 g, 0.53 mol) in toluene (2.5 L, anhydrous) was added POCl 3 (572 mL, 6.26 mol). The resulting mixture was refluxed 15 h, cooled to 10 ambient temperature, and concentrated in vacuo. The residue was dissolved in dichloromethane (1.0 L) and aqueous saturated sodium bicarbonate (500 mL) was carefully added. Solid sodium bicarbonate was then added portion wise until the aqueous layer was basic. The organic layer was washed with brine (300 mL), dried (magnesium sulfate), filtered, and concentrated to afford the title compound as a pale tan solid (76 g, 94%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.41 (s, 1 H), 7.37 15 (s, 1 H), 2.61 (s, 3 H). Step 3: Preparation of 2-chloro-6-methyl-4-(2H-tetrazol-5-yl)pyridine hydrochloride Cl N N IH - NaN Triethylamine hydrochloride (72 g, 0.52 mol) and sodium azide (34 g, 0.52 mol) were added to a solution of 2-chloro-6-methylisonicotinonitrile (76 g, 0.50 mol) in toluene (1.2 L, anhydrous). The 20 mixture was refluxed for 4 hours behind a blast shield. After cooling to ambient temperature, water (1.5 L) was added and the layers were separated, The toluene layer was washed with water (500 mL) and the combined aqueous layers were acidified with 6N hydrochloric acid (100 mL). The resulting precipitate was filtered and dried in vacuo (60 *C) to afford the title compound (105 g). 1H NMR (400 MHz, DMSO-d) 6 ppm 7.92 (s, 1 H), 7.89 (s, 1 H), 2.79 (s, 3 H). 25 Step 4: Preparation of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate o N N, NH O /~ N N 11 Triethylamine (120 mL), 1,1'-bis(diphenylphosphino)ferrocene (8.0 g, 14 mmol), and Pd(OAc) 2 (9.2 g, 40 mmol) were added to a solution of 2-chloro-6-methyl-4-(2H-tetrazol-5-yl)pyridine hydrochloride (88 g, 380 mmol) in methanol (1.5 L, anhydrous) in a pressure reactor. The reactor was 30 evacuated and purged with carbon monoxide gas twice and finally pressurized to 120 PSI and heated 250 WO 2009/016498 PCT/IB2008/002046 to 100 *C for 24 hr (190 PSI reached). An aliquot was taken and analyzed by HPLC revealing consumption of the starting material. After cooling to ambient temp, the mixture was filtered through Celite TM and concentrated in vacuo. Water (700 mL) and aq. saturated NaHCO 3 (200 mL) were added to provide an almost clear solution. 3N hydrochloric acid was added until a pH of 2 was reached. The 5 resulting solid was filtered and dried in vacuo (50 0C) until constant weight (78 g, 94%). 'H NMR (400 MHz, DMSO-de) 6 ppm 8.48 (s, 1 H), 8.15 (s, 1 H), 3.95 (s, 3 H), 2.67 (s, 3 H). Step 5. Preparation of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide 0 N=N O N N NH H NN A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (3.29 g, 15.0 mmol) and 3 10 methoxybenzylamine (6.17 g, 45.0 mmol) was heated at 100 *C with removal of methanol in a stream of nitrogen for 1 hour. A solution of 1 N hydrochloric acid (50 mL) was added. The resulting precipitate was filtered and washed with ethyl ether. The solid was suspended in a solution of 2.5 N sodium hydroxide (30 mL)/water (50 mL) and extracted with ethyl acetate ( 2 x 50 mL). The aqueous layer was cooled in an ice bath and acidified to pH 1 with concentrated hydrochloric acid. The 15 resulting precipitate was filtered and dried to afford the title compound as a white solid (4.69 g, 96%). MS (ES+) m/z 325 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.28 (t, J=6.3 Hz, 1 H), 8.49 (d, J= 0.8 Hz, 1 H), 8.13 (d, J=1.2 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.94-6.90 (m, 2 H), 6.82 (dd, J=8.0, 2.1 Hz, 1 H), 4.51 (d, J=6.3 Hz, 2 H), 3.73 (s, 3 H), 2.68 (s, 3 H). Step 6. Preparation of tert-butyl (trans)-4-((5-(2-((3-methoxybenzvl)carbamoyl)-6-methylpyridin-4-yl) 20 2H-tetrazol-2-vl)methvl)cyclohexylcarbamate a NN H -N N N O H 0 0 N N-(3-Methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (1.62 g, 5.0 mmol), polymer supported triphenylphosphine (3.49 g, 7.5 mmol), and terd-butyl trans-(4 hydroxymethyl)cyclohexylcarbamate (1.38 g, 6.0 mmol) were suspended in tetrahydrofuran (100 mL). 25 Di-ted-butyl azodicarboxylate (1.73 g, 7.5 mmol) was added. The mixture was allowed to stir for 18 hours. The reaction mixture was filtered and the resin washed with THF (100 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2). Combined fractions were concentrated onto silica and repurified by silica column chromatography (heptane/EtOAc, 2/1; 1/1). Combined fractions were concentrated. The resulting solid 30 was slurried in heptane and filtered to afford the title compound as a white solid (1.824 g, 68%). MS (ES+) m/z 536 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 9.23 (t, J=6.3 Hz, 1 H), 8.40 (d, J=0.8 Hz, 251 WO 2009/016498 PCT/IB2008/002046 1 H), 8.05 (d, J=1.1 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.86 - 6.90 (m, 2 H), 6.79 (dd, J=8.2, 1.9 Hz, 1 H), 6.68 (d, J=7.8 Hz, 1 H), 4.63 (d, J=7.0 Hz, 2 H), 4,48 (d, J=6.3 Hz, 2 H), 3.70 (s, 3 H), 3.13 (br. s., 1 H), 2.64 (s, 3 H), 1.90 (br. s., 1 H), 1.71 - 1.77 (m, 2 H), 1.53 - 1.59 (m, 2 H), 1.33 (s, 9 H), 1.06 1.14 (m, 4 H). 5 Step 7. Preparation of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide 0 N " 1 H N N
NH
2 0 N tert-Butyl (trans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexylcarbamate (1.82 g, 3.40 mmol) was dissolved in dichloromethane (20 mL) and 10 trifluoroacetic acid (5.05 mL, 68.0 mmol) was added. The mixture was allowed to stand for 2 hours and was then concentrated. The residue was dissolved in dichloromethane (150 mL) and washed with 1 N NaOH solution (2 x 40 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with heptane and filtered to afford the title compound as a white solid (1.407 g, 95%). MS (ES+) m/z 436 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.23 (t, J=6.3 Hz, 1 15 H), 8.39 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.2 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.86 (m, 2 H), 6.79 (dd, J=8.2, 1.9 Hz, 1 H), 4.62 (d, J=7.1 Hz, 2 H), 4.48 (d, J=6.3 Hz, 2 H), 3.70 (s, 3 H), 2.64 (s, 3 H), 2.45 - 2.37 (m, 1 H), 1.96 - 1.84 (m, 1 H), 1.71 (d, J=12.0 Hz, 2 H), 1.53 (d, J=12.2 Hz, 2 H), 1.37 (br. s., 2 H), 1.07 (q, J=12.8 Hz, 2 H), 1.01 - 0.88 (m, J=10.6, 10.6, 10.6 Hz, 2 H). Example 154 20 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide 0, N 0 /H -N N N H O 0 N Triethylamine (0.096 mL, 0.690 mmol) and methane sulfonyl chloride (0.021 mL, 0.276 mmol) were added to a solution of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol 25 5-yl)-6-methylpicolinamide (prepared as described in Example 153) (100.0 mg, 0.230 mmol) in dichloromethane (2 mL). The mixture was stirred for 2 hours at room temperature. Volatiles were removed under a nitrogen stream. The residue was purified by reverse phase preparative HPLC (5% 95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (28.2 mg, 24%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.148 min., m/z 514 (M+H). 'H NMR (400 MHz, DMSO 30 d 6 ) 6 ppm 0.95 - 1.32 (m, 4 H), 1.49 - 1.69 (m, 2 H), 1.78 - 2.04 (m, 3 H), 2.65 (s, 3 H), 2.86 (s, 3 H), 252 WO 2009/016498 PCT/IB2008/002046 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.77 - 6.82 (m, 1 H), 6.90 (m, 2 H), 6.93 (s, 1 H), 7.12 - 7.29 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.04 - 9.31 (m, 1 H). Example 155 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(ethylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 5 methylpicolinamide O N N ' H O 0 N Triethylamine (0.096 mL, 0.690 mmol) and ethane sulfonyl chloride (44.3 mg, 0.344 mmol) were added to a solution of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol 5-yl)-6-methylpicolinamide (prepared as described in Example 153) (100.0 mg, 0.230 mmol) in 10 tetrahydrofuran (2 mL). The mixture was stirred overnight at room temperature. Volatiles were removed under a nitrogen stream. The residue was purified by reverse phase preparative HPLC (5% 95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (9.9 mg, 8%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.252 min., m/z 528 (M+H). 'H NMR (400 MHz, DMSO d 6 ) 6 ppm 0.96 - 1.36 (m, 7 H), 1.52 - 1.70 (m, 2 H), 1.78 - 1.90 (m, 2 H), 1.89 - 2.10 (m, 1 H), 2.65 (s, 15 3 H), 2.94 - 3.09 (m, 1 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.63 (d, J=6,6 Hz, 2 H), 6.73 - 6.84 (m, 1 H), 6.86 - 6.92 (m, 2 H), 6.92 - 7.01 (m, 1 H), 7.15 - 7.27 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.10 - 9.25 (m, 1 H). Example 156 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(cyclopropanesulfonamido)cyclohexyl)methyl)-2H-tetrazol 20 5-yl)-6-methylpicolinamide H N NO N H O O N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (ethylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 155) by reaction with cyclopropane sulfonyl chloride and afforded 22.3 mg (18%) as a solid. LC/MS (5%-95% 25 CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.310 min., m/z 540 (M+H). 'H NMR (400 MHz, DMSO d 6 ) 6 ppm 0.80 - 0.95 (m, 4 H), 1.04 - 1.33 (m, 4 H), 1.51 - 1.68 (m, 2 H), 1.83 - 2.01 (m, 2 H), 2.41 2.55 (m, 1 H), 2.65 (s, 3 H), 2.96 - 3.14 (m, 1 H), 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.64 (d, J=6.6 Hz, 2 H), 6.73 - 6.84 (m, 1 H), 6.86 - 6.93 (m, 2 H), 6.93 - 7.02 (m, 1 H), 7.13 - 7.29 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.11 - 9.27 (m, 1 H). 253 WO 2009/016498 PCT/IB2008/002046 Example 157 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(butylsulfonamido)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide O N' N N N' H O 0 N 5 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (ethylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 155) by reaction with butane sulfonyl chloride and afforded 45.6 mg (36%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min, 95% CH 3 CN, 1.5 min.): 3.574 min., 556 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.77 - 0.91 (m) 1.07 - 1.47 (m) 1.48 - 1.91 (m) 1.91 - 2.05 (m, 1 H), 2.65 (s, 3 H), 2.83 - 3.01 (m) 10 3.48 - 3.65 (m, 1 H), 3.71 (s, 3 H), 4.49 (d, J=6.59 Hz, 2 H), 4.66 (d, J=7.32 Hz, 2 H), 6.76 - 6.82 (m, 1 H), 6,87 - 6.97 (m) 7.17 - 7.26 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.15 - 9.25 (m). Example 158 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 0 N 'NN HN N N H O N 15 Acetic anhydride (0.033 mL, 0.344 mmol) and silica-bound 4-(dimethylamino)pyridine (833.0 mg, 0.575 mmol, 0.69 mmol/g loading) were added to a solution of N-(3-methoxybenzyl)-4-(2-(((trans) 4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 153) (50.1 mg, 0.115 mmol) in dichloromethane (2 mL). The reaction mixture was agitated overnight at 20 room temperature, filtered, and washed with N,N-dimethylformamide. The filtrate was concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min) to afford the title compound (22.4 mg, 41%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2,994 min., m/z 478 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.99 1.28 (m, 4 H), 1.60 (m, 2 H), 1.73 (s, 3 H), 1.74 - 1.81 (m, 3 H), 1.89 - 2.06 (m, 1 H), 2.65 (s, 3 H), 3.71 25 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.75 - 6.83 (m, 1 H), 6.86 - 6.98 (m, 2 H), 7.13 - 7.30 (m, 1 H), 7.63 (s, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.06 - 9.25 (m, 1 H). Example 159 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-isobutyramidocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 254 WO 2009/016498 PCT/IB2008/002046 0 N ' , H N N N H I0) N The title compound was prepared in a similar manner to N-(3-Methoxybenzyl)-4-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 158) by reaction with isobutyric anhydride and afforded 22.6 mg (39%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 5 95% CH 3 CN, 1.5 min.): 3.325 min., m/z 506 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 0.93 (s, 3 H), 0.94 (s, 3 H), 1.02 - 1.26 (m, 4 H), 1.54 - 1.66 (m, 2 H), 1.69 - 1.81 (m, 2 H), 1.86 - 2.04 (m, 1 H), 2.18 - 2.36 (m, 1 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.65 (d, J=7.3 Hz, 1 H), 6.71 6.83 (m, 1 H), 6.86 - 6.98 (m, 2 H), 7.13 - 7.30 (m, 1 H), 7.38 - 7.55 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.12 - 9.26 (m, 1 H). 10 Example 160 2-((trans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2-yl)methyl) cyclohexylamino)-2-oxoethyl acetate 0 N N HN N N O H 0 N O Triethylamine (651 pL, 6.43 mmol), 4-(dimethylamino)pyridine (78.5 mg, 0.64 mmol), and 15 acetoxyacetyl chloride (415 pL, 3.86 mmol) were added to a solution of N-(3-methoxybenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 153) (1.400 g, 3.21 mmol) in dichloromethane (60 mL).. The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (150 mL) and washed with saturated aq. sodium bicarbonate solution (2 x 40 mL). The organic layer was dried over 20 sodium sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2). Fractions were concentrated and the oily residue was partially concentrated from a mixture of dichloromethane/heptane/ethyl ether. The resulting slurry was filtered to afford the title compound as a white solid (1.513 g, 88%). MS (ES+) m/z 536 (M+H). IH NMR (400 MHz, DMSO-de) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.82 25 (d, J=7.9 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.86 (m, 2 H), 6.79 (dd, J=7.9, 2.0 Hz, 1 H), 4.65 (d, J=7.0 Hz, 2 H), 4.48 (d, J=6.4 Hz, 2 H), 4.35 (s, 2 H), 3.70 (s, 3 H), 3.49 (br. s., 1 H), 2.65 (s, 3 H), 2.03 (s, 3 H), 1.95 (br. s., 1 H), 1.78 - 1.71 (m, 2 H), 1.63 - 1.56 (m, 2 H), 1.21 - 1.11 (m, 4 H). Example 161 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl) 30 6-methylpicolinamide 255 WO 2009/016498 PCT/IB2008/002046 0_< N 'N H N N N OH H O N 2-((trans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexylamino)-2-oxoethy acetate (prepared as described in Example 160) (1.50 g, 2.80 mmol) was dissolved in tetrahydrofuran (100 mL). Lithium hydroxide (201 mg, 8.40 mmol) followed by 5 water (35 mL) were added. The mixture was stirred for 1 hour and then the tetrahydrofuran was removed in vacuo. The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated to afford a foaming solid. The residue was dissolved in methanol (10 mL) and seeded. The resulting slurry was filtered to afford the title compound as a white crystalline solid (1.233 g, 89%). MS (ES+) m/z 494 (M+H). IH NMR (400 10 MHz, DMSO-d) 6 ppm 9.23 (t, J=6.4 Hz, 1 H), 8.40 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.86 (m, 2 H), 6.79 (dd, J=8.2, 1.9 Hz, 1 H), 5.36 (t, J=5.8 Hz, 1 H), 4.65 (d, J=7.0 Hz, 2 H), 4.48 (d, J=6.4 Hz, 2 H), 3.72 (d, J=5.8 Hz, 2 H), 3.70 (s, 3 H), 3.59 - 3.48 (m, 1 H), 2.65 (s, 3 H), 2.00 - 1.89 (m, 1 H), 1.71 (d, J=10.6 Hz, 2 H), 1.59 (d, J=13.6 Hz, 2 H), 1.32 1.09 (m, 4 H). 15 Example 162 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide O N 'NN H N N N OH H O N A mixture of 2-hydroxy isobutyric acid (10 mg, 0.10 mmol) and 1-hydroxybenzatriazole (15 20 mg, 0.11 mmol) in 2- methyl tetrahydrofuran (2 mL) for was stirred for 5 minutes. N-(3 Methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 153) (0.050 g, 0.09 mmol), triethylamine (0.015 mL, 0.11 mmol), and polymer supported carbodiimide (0.11 g, 0.14 mmol) were added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was washed with water (3 x 5 mL) 25 followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (21 mg, 45%). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 2 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.8 Hz, 1 H), 4.65 (d, J=6.6 Hz, 2 H), 4.49 (d, J=5.9 Hz, 2 H), 3.71 (s, 3 H), 3.21 - 3.35 (m, 1 H), 2.65 (s, 3 H), 1.91 - 2.05 (m, 1 H), 1.72 (d, J=1 1.7 Hz, 2 H), 1.60 (d, J=1 1.7 Hz, 2 30 H), 1.06 - 1.33 (m, 10 H). 256 WO 2009/016498 PCT/IB2008/002046 Example 163 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-((S)-2-hydroxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 0 N 'NN HN N N OH O N H 5 A mixture of (S)-2-acetoxypropanoic acid (13 mg, 0.10 mmol) and 1-hydroxybenzatriazole (16 mg, 0.12 mmol) in 2-methyl tetrahydrofuran (2 mL) was stirred for 5 minutes. N-(3-Methoxybenzyl)-4 (2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 153) (0.055 g, 0.10 mmol), triethylamine (0.017 mL, 0.12 mmol), and polymer supported carbodiimide (0.12 g, 0.15 mmol) were added. The mixture was stirred for 18 hours at room 10 temperature and was then filtered. The filtrate was concentrated, and the residue was dissolved in acetonitrile (5 mL). Aqueous sodium hydroxide solution (2.5 N, 1.0 mL) was added and the mixture was stirred for 18 hours at room temperature. The acetonitrile was removed in vacuo and the aqueous phase was acidified to pH 6 with an aqueous 10% solution of hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (2 15 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (23 mg, 45%). H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.31 (d, J=8.1 Hz, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=7.3 Hz, 1 H), 5.32 (d, J=5.1 Hz, 1 H), 4.65 (d, J=6.6 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.83 - 3.96 (m, 1 H), 3.71 (s, 3 H), 3.42 - 3.55 (m, 1 20 H), 2.65 (s, 3 H), 1.97 (d, J=2.9 Hz, 1 H), 1.72 (d, J=6.6 Hz, 2 H), 1.61 (d, J=12.4 Hz, 2 H), 0.97 - 1.34 (m, 7 H). Example 164 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide 0 ~~N,N" H NO N H NH2 0 N 25 A solution of 1-hydroxybenzotriazole (3.2 mg, 0.024 mmol) in N,N-dimethylformamide (2 mL) was added to 3-(tert-butoxycarbonyl)propanoic acid (27.2 mg, 0,144 mmol). Carbodiimide resin (138 mg, 0.18 mmol, 1.30 mmol/g loading), dichloromethane (2 mL), N-(3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 30 153) (52.3 mg, 0.120 mmol), and N-methylmorpholine (0.066 mL, 0.60 mmol) were added. The mixture was agitated at room temperature overnight. The reaction mixture was filtered washing with 257 WO 2009/016498 PCT/IB2008/002046 N,N-dimethylformamide followed by dichloromethane, and volatiles were removed under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min). After concentration, the resulting intermediate was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1/1) and stirred for 1 hour. The reaction mixture was filtered and concentrated. 5 The residue was suspended in dichloromethane and neutralized using MP-carbonate resin to afford the title compound (10 mg, 16%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.642 min, m/z 507 (M+H). Example 165 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazo-5-yl) 10 6-methylpicolinamide O N N ON HH N N A", H 0 N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 164) by reaction with 2-methoxyacetic acid to afford 25.6 mg (42%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 15 95% CH 3 CN, 1.5 min.): 3.162 min., m/z 508 (M+H). Example 166 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3-methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 0 N N N H -N0 ZN N H 0 0 N 20 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 164) by reaction with 3-methoxypropanoic acid to afford 24.3 mg (39%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.087 min., m/z 522 (M+H). Example 167 25 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 258 WO 2009/016498 PCT/IB2008/002046 O N 'NN H NO N N NH 2 H O N~ The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 164) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 10.0 mg (17%). LC/MS (5%-95% 5 CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.631 min., m/z 493 (M+H). Example 168 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 0 NN HN N N H OH O N 10 Step 1: Preparation of methyl 4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate \ 0 0 O NH A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 15 methylpicolinamide, Example 153) (1.5 g, 6.8 mmol), tert-butyl trans-(4 hydroxymethyl)cyclohexylcarbamate (3.14 g, 13.7 mmol), and polymer supported triphenylphosphine resin (6.37 g, 13.7 mmol, 2.15 mmol/g loading) in tetrahydrofuran (75 mL) was cooled in an ice bath. Di-tert-butylazodicarboxylate (3.15 g, 13.7 mmol) was added and the mixture was stirred with cooling for 30 minutes. The mixture was then allowed to warm to room temperature and stir for 18 hours. The 20 reaction mixture was filtered and the resin was washed with tetrahydrofuran and methanol. The filtrate was concentrated. The residue was dissolved in methanol (25 mL) and treated with 4N hydrochloric acid in dioxane (10.2 mL, 40.8 mmol) for 18 hours at room temperature. The reaction mixture was concentrated and the residue washed with ethanol to afford the hydrochloride salt of the product as a solid (2.09 g, 84%). MS (ES+) m/z 331 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 1.18 (s, 2 H), 25 1.26 - 1.42 (m, 2 H), 1.65 (d, J=1 1.28 Hz, 2 H), 1.97 (s, J=9.94 Hz, 3 H), 2.64 (s, 3 H), 2.89 (br. s., 1 H), 3.91 (s, 3 H), 4.67 (d, J=6.71 Hz, 2 H), 8.11 (s, J=1.34 Hz, 1 H), 8.25 (br. s., 2 H), 8.39 (s, 1 H). 259 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of 4-(2-(((trans)-4-(3-hydroxvpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid 0 HO H N NNN OH N N - N-N~ 0 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (775 mg, 2.04 5 mmol) was added to a solution of methyl 4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate (500 mg, 1.36 mmol), 3-hydroxypropanoic acid (147 mg, 1.63 mmol), and triethylamine (0.23 mL, 1.63 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was allowed to stir at room temperature for 2 days and was then treated with lithium hydroxide (326 mg, 13.6 mmol). The mixture was stirred for 18 hours. The reaction mixture was acidified with the addition 10 of 3 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as a solid Step 3: Preparation of N-(3-methoxybenzyl)-4-(2-(((trans)-4-(3 hydroxypropanamido)cyclohexvl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 0 N' N N N H O H 0 N 15 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (109 mg, 0.289 mmol) was added to a solution of 4-(2-(((trans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinic acid (50 mg, 0.13 mmol), 3-methoxyphenylmethanamine (50 mg, 0.36 mmol), and triethylamine (0.07 mL, 0.48 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase 20 preparative HPLC. Fractions containing the product were passed through a carbonate cartridge eluting with methanol and then concentrated to afford the title compound as a white solid (16 mg, 24%). MS (ES+) m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 0.99 - 1.23 (m, 4 H), 1.53 1.64 (m, 2 H), 1.68 - 1.81 (m, 2 H), 1.86 - 2.03 (m, 2 H), 2.15 (t, J=6.59 Hz, 2 H), 2.44 - 2.48 (m, 1 H), 2.64 (s, 3 H), 3.54 (t, J=6.22 Hz, 2 H), 3.70 (s, 3 H), 4.48 (d, J=6.59 Hz, 2 H), 4.63 (d, J=6.59 Hz, 2 H), 25 6.78 (d, J=8.05 Hz, 1 H), 6.85 - 6.91 (m, 1 H), 7.12 - 7.25 (m, 2 H), 7.58 (d, J=8.05 Hz, 1 H), 8.04 (s, 1 H), 8.39 (s, 1 H), 9.18 (t, J=6.22 Hz, 1 H). Example 169 1 -((trans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexyl)-3-methylurea 260 WO 2009/016498 PCT/IB2008/002046 01 N,N / 00 N N N H H 0 N Methyl isocyanate (1 mL, 4M solution in dichloromethane) and silica-bound 4 (dimethylamino)pyridine (833.0 mg, 0.575 mmol, 0.69 mmol/g loading) were added to a solution of N (3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 5 (prepared as described in Example 153) (50.0 mg, 0.115 mmol) in dichloromethane (1 mL). The mixture was agitated overnight at room temperature and was then filtered washing with N,N dimethylformamide. The filtrate was concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (22.8 mg, 40%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.963 min., 10 m/z 493 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.87 - 1.30 (m, 4 H), 1.48 - 1.68 (m, 2 H), 1.71 1.85 (m, 2 H), 1.95 (s, 1 H), 2.38 - 2.53 (m, 3 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 5.42 - 5.55 (m, 1 H), 5.58 - 5.72 (m, 1 H), 6.71 - 6.84 (m, 1 H), 6.86 - 6.95 (m, 2 H), 7.14 - 7.32 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.19 (s, 1 H). Example 170 15 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide F O -N NH
NH
2 0 N Step 1: Preparation of 6-methyl-4-(2H-tetrazol-5-Vl)picolinic acid 0 N , ,NH HO - N 20 A solution of lithium hydroxide monohydrate (4.1 g, 100 mmol) in water (100 mL) was added to a suspension of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) in tetrahydrofuran (300 mL). The mixture was heated to reflux overnight, concentrated in vacuo, and dissolved in water. The mixture was cooled in an ice/water bath 25 and acidified with 1 N hydrochloric acid. The resulting precipitate was filtered, washed with water, and air dried to afford the title compound as an odd-white solid (10.35 g, 100%). MS (ES+) m/z 206 261 WO 2009/016498 PCT/IB2008/002046 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 8.41 (d, J=0.8 Hz, 1 H), 8.06 (d, J=1.1 Hz, 1 H), 2.62 (s, 3 H). Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide 0 N N NH F N... 5 A mixture of 6-methyl-4-(2H-tetrazol-5-yl)picolinic acid (27 g, 0.132 mol), 4-fluoro-3 methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3 methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (26.5 g, 0.138 mol), tetrahydrofuran (445 mL), and 1-hydroxybenzotriazole (18.6 g, 0.138 mmol) was cooled in an ice bath. N-Methylmorpholine (43.5 mL, 0.396 mmol) followed by 10 dimethylsulfoxide (335 mL) and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (26.5 g, 0.138 mmol) were added. The mixture was allowed to warm to room temperature overnight. Dimethylsulfoxide (100 mL) was added followed by 1N hydrochloric acid (400 mL) with ice bath cooling. After stirring for 45 min, the precipitate was filtered. The resulting solid was slurried in ethyl acetate, filtered, and dried in vacuo to afford the title compound (31.98 g). MS (ES+) m/z 343 (M+H), 15 1H NMR (400 MHz, DMSO-d) 6 ppm 9.30 (t, J=6.4 Hz, 1 H), 8.47 (d, J=1.1 Hz, 1 H), 8.09 (d, J=1.2 Hz, 1 H), 7.18 (dd, J=8.5, 1.9 Hz, 1 H), 7.14 (dd, J=11.7, 8.3 Hz, 1 H), 6.90 (ddd, J=8.2, 4.4, 2.0 Hz, 1 H), 4.50 (d, J=6.3 Hz, 2 H), 3.82 (s, 3 H), 2.68 (s, 3 H) Step 3: Preparation of tert-butyl (trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-vl)methyl)cyclohexylcarbamate F ,N. /0 N N N' O NH - N 0 H 0 N 20 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (1.71 g, 5.0 mmol), polymer supported triphenylphosphine (3.49 g, 7.5 mmol), and tert-butyl trans-(4 hydroxymethyl)cyclohexylcarbamate (1.38 g, 6.0 mmol) were suspended in tetrahydrofuran (100 mL). Di-tert-butyl azodicarboxylate (1.73 g, 7.5 mmol) was added. The mixture was allowed to stir for 18 25 hours. The reaction mixture was filtered and the resin washed with tetrahydrofuran (100 mL). The filtrate was concentrated, The crude product was purified by silica column chromatography
(CH
2
CI
2 /methanol, 100/1; 100/2). Combined fractions were concentrated onto silica and repurified by silica column chromatography (heptane/EtOAc, 2/1; 1/1). Combined fractions were concentrated and triturated with heptane to afford the title compound as a white solid (1.903 g, 69%). MS (ES+) m/z 554 30 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.2 Hz, 1 H), 7.15 (dd, J=8.7, 1.9 Hz, 1 H), 7.11 (dd, J=11.7, 8.3 Hz, 1 H), 6.87 (ddd, J=8.3, 4.3, 2.0 262 WO 2009/016498 PCT/IB2008/002046 Hz, 1 H), 6.68 (d, J=7.7 Hz, 1 H), 4.63 (d, J=7.0 Hz, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 3.14 (br. s., 1 H), 2.64 (s, 3 H), 1.89 (br. s., 1 H), 1.78 - 1.70 (m, 2 H), 1.59 - 1.53 (m, 2 H), 1.33 (s, 9 H), 1.16 - 1.04 (m, 4 H). Step 3: Preparation of N-(4-fluoro-3-methoxvbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H 5 tetrazol-5-yl)-6-methylpicolinamide F N NH
NH
2 o N tert-Butyl (trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexylcarbamate (1.90 g, 3.43 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.1 mL, 68.6 mmol) was added. The mixture was allowed to stand for 2 10 hours and was then concentrated, The residue was dissolved in dichloromethane (150 mL) and washed with 1 N NaOH solution (2 x 40 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a glass (1.541 g, 98%). MS (ES+) m/z 454 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.25 (t, J=6.4 Hz, 1 H), 8.39 (s, 1 H), 8.05 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=1 1.7, 8.3 Hz, 1 H), 6.87 (ddd, J=8.3, 4.4, 2.0 Hz, 1 H), 4.62 (d, 15 J=7.0 Hz, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 2.64 (s, 3 H), 2.42 (tt, J=10.9, 3.4 Hz, 1 H), 1.95 - 1.84 (m, 1 H), 1.71 (d, J=11.1 Hz, 2 H), 1.53 (d, J=12.5 Hz, 2 H), 1.37 (br. s., 2 H), 1.07 (q, J=12.1 Hz, 2 H), 0.94 (q, J=1 1.5 Hz, 2 H). Example 171 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinamide F o~
N
4 "
-
N ,, NH N H o N Triethylamine (944 pL, 6.77 mmol), 4-(dimethylamino)pyridine (83 mg, 0.68 mmol), and acetyl chloride (289 pL, 4.06 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 25 170) (1.535 g, 3.39 mmol) in dichloromethane (60 mL).. The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (150 mL) and washed with saturated aq. sodium bicarbonate solution (2 x 40 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2; 100/4). Fractions were concentrated. The resulting solid was 263 WO 2009/016498 PCT/IB2008/002046 triturated with ethyl ether and filtered to afford the title compound as a white solid (1.370 g, 82%). MS (ES+) m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.2 Hz, 1 H), 7.67 (d, J=7.8 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.6, 8.4 Hz, 1 H), 6.87 (ddd, J=8.3, 4.4, 2.0 Hz, 1 H), 4.64 (d, J=7.1 Hz, 2 H), 4.47 (d, J=6.3 Hz, 2 H), 3.79 5 (s, 3 H), 3.47 - 3.38 (m, 1 H), 2.65 (s, 3 H), 1.98 - 1.90 (m, 1 H), 1.78 - 1.72 (m, 2 H), 1.72 (s, 3 H), 1.62 - 1.55 (m, 2 H), 1.19 - 1.03 (m, 4 H). Example 172 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F 0 N',N NH N N H NH 2 0 N 10 0-(7-Azabenzotriazole-1 -yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (75.0 mg, 0.198 mmol), 3-(tert-butoxycarbonyl)propanoic acid (31.2 mg, 0.165 mmol), and diisopropylethylamine (0.057 mL, 0.330 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 15 170) (74.8 mg, 0.165 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred overnight at room temperature. Volatiles were removed under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound (30.5mg, 35%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 3.69 min., m/z 525 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.96 - 1.28 (m), 1.50 - 1.84 (m), 1.88 - 2.05 (m), 2.10 (t, J=6.6 Hz, 2 H), 2.65 (s, 3 20 H), 2.69 (t, J=6.6 Hz, 2 H), 3.27 (br. s.), 3.46 (br. s.), 3.80 (s, 3 H), 4.48 (d, J=5.9 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 6.78 - 6.95 (m), 7.04 - 7.21 (m), 7.66 - 7.75 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.14 9.27 (m, 1 H). Example 173 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-methoxyacetamido)cyclohexyl)methyl)-2H 25 tetrazol-5-yl)-6-methylpicolinamide F -- ,N ONH NN N O H 0 N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 172) by reaction with 2-methoxyacetic acid to afford 41.5 mg (48%). LC/MS (5%-100% CH 3
CN/H
2 0, 264 WO 2009/016498 PCT/IB2008/002046 10.0 min.): 4.71 min., m/z 526 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.35 (m, 4 H), 1.55 - 1.80 (m, 4 H), 1.87 - 2.03 (m, 1 H), 2.65 (s, 3 H), 3.44 - 3.63 (m, 1 H), 3.72 (s, 3 H), 3.80 (s, 3 H), 4.48 (d, J=6.6 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 6.84 - 6.92 (m, 1 H), 7.06 - 7.20 (m, 2 H), 7.42 - 7.50 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.11 - 9.27 (m, 1 H). 5 Example 174 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(3-methoxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide F N O N ON N 0 NH N 1 ~ H 0 0 N The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-4-(2 10 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 172) by reaction with 3-methoxypropanoic acid to afford 52.7 mg (59%). LC/MS (5%-100%
CH
3
CN/H
2 0, 10.0 min.): 4.61 min., m/z 540 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.02 - 1.25 (m, 4 H), 1.56 - 1.83 (m, 4 H), 1.90 - 2.02 (m, 1 H), 2.23 (t, J=6.2 Hz, 2 H), 2.65 (s, 3 H), 3.28 (s), 3.47 (t, J=6.6 Hz, 2 H), 3.80 (s, 3 H), 4.48 (d, J=6.6 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 6.84 - 6.92 (m, 1 H), 15 7.05 - 7.20 (m, 2 H), 7.61 - 7.68 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.18 - 9.26 (m, 1 H). Example 175 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-aminoacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F /N N NH N N NH 2 / \ H o N 20 The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 172) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 34.5 mg (41%). LC/MS (5%-100%
CH
3
CN/H
2 0, 10.0 min.): 3.66 min., m/z 511 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.27 (m, 4 H), 1.53 - 1.84 (m, 4 H), 1.91 - 2.03 (m, 1 H), 2.65 (s, 3 H), 3.01 (s, 2 H), 3.28 (br. s.), 3.41 - 3.58 25 (m, 1 H), 3.80 (s, 3 H), 4.48 (d, J=6.6 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 6.85 - 6.91 (m, 1 H), 7.06 7.20 (m, 2 H), 7.53 - 7.61 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.16 - 9.27 (m, 1 H). 265 WO 2009/016498 PCT/IB2008/002046 Example 176 2-((trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexylamino)-2-oxoethyl acetate F NH, N 0 O NH N-'N N kO H o N 0 5 The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 172) by reaction with 2-acetoxyacetic acid to afford 48.0 mg (53%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.76 min., m/z 554 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.26 (m, 4 H), 1.56 - 1.81 (m, 4 H), 1.90 - 2.02 (m, 1 H), 2.04 (s, 3 H), 2.65 (s, 3 H), 3.42 - 3,56 (m, 1 H), 3.80 (s, 3 H), 10 4.36 (s, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 6.84 - 6.93 (m, 1 H), 7.06 - 7.20 (m, 2 H), 7.74 - 7.82 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.17 - 9.25 (m, 1 H). Example 177 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F ,N /N N NH NN OH / \ H O N 15 The title compound was prepared in a similar manner to N-(4-fluoro-3-methoxybenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 172) by reaction with 2-hydroxyacetic acid to afford 41.0 mg (49%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.41 min., m/z 512 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.39 (m, 4 H), 1.53 20 - 1.79 (m, 4 H), 1.88 - 2.05 (m, 1 H), 2.65 (s, 3 H), 3.48 - 3.61 (m, 1 H), 3.73 (s, 3 H), 3.80 (s, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 4,65 (d, J=7.3 Hz, 2 H), 6.85 - 6.92 (m, 1 H), 7.06 - 7.19 (m, 2 H), 7.33 - 7.40 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9,17 - 9.26 (m, 1 H). Example 178 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H 25 tetrazol-5-yl)-6-methylpicolinamide 266 WO 2009/016498 PCT/IB2008/002046 F 0 \ / N- O NH N N H OH 0 N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (3-hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 168) by reaction with 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the 5 synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazo-5 yl)pyrimidine-4-carboxamide, Example 1) to afford 25 mg (37%) of a white solid. MS (ES+) m/z 526 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.05 - 1.25 (m, 4 H), 1.57 - 1.68 (m, 2 H), 1.73 - 1.84 (m, 2 H), 1.92 - 2.04 (m, 1 H), 2.19 (t, J=6.59 Hz, 2 H), 2.54 (s, 2 H), 2.67 (s, 3 H), 3.53 - 3.62 (m, 2 H), 3.82 (s, 3 H), 4.51 (d, J=5.86 Hz, 2 H), 4.67 (d, J=7.32 Hz, 2 H), 6.86 - 6.95 (m, 1 H), 7.06 - 7.25 (m, 2 10 H), 7.62 (d, J=7.32 Hz, 1 H), 8.07 (s, 1 H), 8.43 (s, 1 H), 9.24 (t, J=6.22 Hz, 1 H). Example 179 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2 methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F I N O -N NH N OH H O N 15 Step 1: Preparation of methyl 4-(2-(((trans)-4-(2-hydroxy-2-methylpropanamido)cvclohexvl)methyl)-2H tetrazol-5-yl)-6-methylpicolinate 0 0 O N OH N- C IO 0 A mixture of 2-hydroxy isobutyric acid (25 mg, 0.24 mmol) and 1 -hydroxybenzatriazole (37 mg, 0.27 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes. 4-(2-(((trans)-4 20 Aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide, Example 168) (0.10 g, 0.23 mmol), triethylamine (0.038 mL, 0.27 mmol), and polymer supported carbodiimide (0.27 g, 0.34 mmol) were added. The mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered. The filtrate was washed with 25 water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. 267 WO 2009/016498 PCT/IB2008/002046 The residue was purified by silica column chromatography (0-50% ethyl acetate/heptane) to afford the title compound (65 mg, 69%). Step 2: Preparation of 4-(2-(((trans)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinic acid 0 HO N OH - N- 0 5 Aqueous sodium hydroxide (2.5 N, 1.0 mL) was added to a solution of methyl 4-(2-(((trans)-4 (2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (65 mg, 0.16 mmol) in acetonitrile (2 mL), and the mixture was stirred for 1 hour at room temperature. The acetonitrile was removed in a stream of nitrogen. Water (1 mL) was added to the residue and the 10 mixture was acidified to pH 6 with 10% aqueous hydrochloric acid. The resulting solid was collected by filtration, washed with water (2 x 2 mL), and dried to afford the title compound (53 mg, 84%). MS (ES+) m/z 403 (M+H). Step 3: Preparation of N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2 methylpropanamido)cyclohexvl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F - N /0 N' N NH N OH / \ H 0 N 15 A mixture of 4-(2-(((trans)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H-tetrazol 5-yl)-6-methylpicolinic acid (0.040 g, 0.10 mmol) and 1-hydroxybenzatriazole (21 mg, 0.12 mmol) in N,N-dimethylformamide was stirred for 15 minutes. 4-Fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4 20 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (27 mg, 0.16 mmol) was then added followed by polymer supported carbodiimide (0.135 g, 0.15 mmol). The mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered, and the filtrate was extracted by ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (2 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue 25 was purified by reverse phase preparative HPLC to afford the title compound (8.3 mg, 15%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (s, 1 H), 8.41 (br. s., 1 H), 8.06 (br. s,, 1 H), 7.06 - 7.28 (m, 2 H), 6.88 (d, J=8.8 Hz, 1 H), 6.43 (br. s., 1 H), 5.25 (br. s., 1 H), 4.67 (d, J=3.7 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.80 (s, 3 H), 3.60 (d, J=9.5 Hz, 1 H), 2.66 (s, 3 H), 2.05 (s, 1 H), 1.72 (d, J=1 1.7 Hz, 2 H), 1.60 (d, J=7.3 Hz, 2 H), 1.10 - 1.34 (m, 9 H). 268 WO 2009/016498 PCT/IB2008/002046 Example 180 N-(3-Ethoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide 0 N NQ ONN -NH N' \\ \- H O 0 N 5 Step 1: Preparation of 6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cvclohexyl)methyl)-2H-tetrazol-5 yl)picolinic acid 0 HO N N O
-
N' H Diisopropylethylamine (0.59 mL, 3.4 mmol) and methanesulfonyl chloride (0.16 mL, 2.1 mmol) were added to a solution of methyl 4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 10 methylpicolinate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-4-(2 (((trans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 168) (125 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL). The mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in tetrahydrofuran (8 mL). A 4N aqueous solution of lithium hydroxide (2 mL) was added and the 15 mixture was allowed to stir for 4 hours. The reaction mixture was concentrated and purified by reverse phase preparative HPLC (20-60% acetonitrile/water) to afford the title compound (42 mg, 25%). Step 2: Preparation of (3-ethoxyphenvl)methanamine O
NH
2 Lithium aluminum hydride (59.5 g) was added to anhydrous ethyl ether (900 mL) cooled to 10 20 *C. A solution of 3-ethoxybenzonitrile (35.5 g) in anhydrous ethyl ether (100 mL) was added over 1.25 hours, and the mixture was stirred for 4.5 hours, The reaction mixture was quenched with water (60 mL) and was stirred for 1.25 hours. A 15% aqueous solution of sodium hydroxide (60 mL) was added followed by ether (500 mL) and water (180 mL). The slurry was filtered. The filtrate was dried over sodium sulfate and concentrated to afford the title compound as an oil (35.3 g). MS (ES+) m/z 152 25 (M+H). 'H NMR (400 MHz, CDC13) 6 ppm 7.20 (t J=8.1, 1 H), 6.87-6.72 (m, 3 H), 4.00 (q, J=6.9, 2 H), 3.78 (s, 2 H), 1.38 (t, J=7.2, 3 H) 269 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide NN NH N' H O 0 N In a 2 dram vial with a magnetic stir bar, 6-methyl-4-(2-(((trans)-4 5 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinic acid (70 mg, 0.177 mmol) was dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (0.19 mL, 1.06 mmol) and (3 ethoxyphenyl)methanamine (33.4 mg, 0.221 mmol) were added and the mixture was stirred for 30 minutes. O-(1H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (128 mg, 0.398 mmol) was added and stirring continued at room temperature overnight. The reaction mixture was 10 purified by reverse phase preparative HPLC to afford the title compound (27.2 mg). LC/MS (5%-95%
CH
3
CN/H
2 0, 5 min.) 3.54 min, m/z 514 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) o ppm 1.06 - 1.33 (m, 8 H), 1.54 - 1.65 (m, 3 H), 1.82 - 1.98 (m, 3 H), 2.45 - 2.50 (m, 1 H), 2.50 - 2.53 (m, 1 H), 2.61 - 2.68 (m, 3 H), 2.80 - 2.88 (m, 3 H), 2.97 - 3.08 (m, 1 H), 3.94 - 3.98 (m, 2 H), 4.43 - 4.52 (m, 2 H), 4.58 - 4.69 (m, 2 H), 6.73 - 6.80 (m, 1 H), 6.83 - 6.97 (m, 2 H), 7.15 - 7.26 (m, 1 H), 8.02 - 8.07 (m, 1 H), 8.38 15 8.43 (m, 1 H), 9.14 - 9.23 (m, 1 H). Example 181 N-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide F HO N N H N'e H 0 O N 20 Step 1: Preparation of (5-(aminomethyl)-2-fluorophenyl)methanol HO "'. NH 2 In a 250 round bottomed flask with a magnetic stir bar, 4-fluoro-3-formylbenzonitrile (1.50 g, 10.06 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled in an ice bath to 0 *C and lithium aluminum hydride (573 mg, 15.1 mmol) was added. The reaction mixture was stirred at 0 25 *C for 3 hours and then was allowed to warm to room temperature and stir overnight. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (478 mg, 30%). MS (ES+) m/z 156 (M+H). 'H NMR (400 MHz, methanol d 4 ) 6 ppm 4.09 (s, 2 H), 4.68 (s, 2 H), 7.13 (dd, J=9.67, 8.59 Hz, 1 H), 7.31 - 7.44 (m, 1 H), 7.56 (dd, J=6.85, 2.28 Hz, 1 H). 270 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide F HO N~~ NH N H O The title compound was prepared in a similar manner to N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4 5 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 180) by reaction with (5-(aminomethyl)-2-fluorophenyl)methano to afford 14.1 mg. 1 H NMR (400 MHz, CD 3 0D) 6 ppm 1.28 (d, J=11.6 Hz, 4 H), 1.34 (d, 1 H), 1.73 (s, 2 H), 2.67 (s, 3 H), 3.12 - 3.22 (m, 1 H), 4.59 - 4.64 (m, 6 H), 7.02 (s, 1 H), 7.26 - 7.34 (m, 1 H), 7.45 - 7.51 (m, 1 H), 8.09 (d, J=1.1 Hz, 1 H). Example 182 10 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide F
-
,N O NH NH N' S\ H O O N~ The title compound was prepared in a similar manner to N-(3-ethoxybenzyl)-6-methyl-4-(2 (((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 180) by 15 reaction with 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)pyrimidine-4-carboxamide, Example 1) to afford 15.9 mg. 'H NMR (400 MHz, DMSO-de) 6 ppm 1.07 - 1.27 (m, 5 H), 1.61 (d, J=10.3 Hz, 2 H), 1.89 (d, J=10.3 Hz, 2 H), 2.51 (s, 1 H), 2.65 (s, 3 H), 2.86 (s, 3 H), 2.96 - 3.11 (m, 2 H), 3.27 (s, 1 H), 3.80 (s, 3 H), 4.48 (d, J=5.9 Hz, 2 H), 4.64 (d, J=6.6 20 Hz, 2 H), 6.85 - 6.95 (m, 2 H), 7.05 - 7.19 (m, 2 H), 8.03 - 8.07 (m, 1 H), 8.37 - 8.43 (m, 1 H), 9.15 9.25 (m, 1 H). Example 183 N-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide HO NHN 0 H 0 0 N 25 271 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of (3-(aminomethyl)phenyl)methanol HO O
NH
2 To a refluxing (33.8 0C) suspension of lithium aluminum hydride (20.0 g) in anhydrous ethyl ether (300 mL) under nitrogen was added portionwise of 3-cyanobenzaldehyde (10.51 g) over a 2 min 5 period. The resulting slurry was heated at reflux for 10 hours. The reaction mixture was cooled in an ice bath and water (20 mL) was added in 1 mL increments while keeping the temperature < 20 *C. A 15 % sodium hydroxide solution (20 mL) was added in a similar fashion, followed by water (60 mL). The resulting solids were filtered off and washed. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of dichloromethane/methanol/ammonium hydroxide (95/5/0.5, 10 mL), 10 filtered, and purified by silica column chromatography eluting with the same to afford the title compound as a light yellow oil (4.25 g). Step 2: Preparation of N-(3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide N HO NN N 0 NH /' \\H 1 H 0 0 N 15 The title compound was prepared in a similar manner to N-(3-ethoxybenzyl)-6-methyl-4-(2 (((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 180) by reaction with (3-(aminomethyl)phenyl)methanol to afford 27.2 mg. 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.28 (m, 5 H), 1.61 (d, J=10.3 Hz, 3 H), 1.89 (d, J=1 1.0 Hz, 2 H), 2.65 (s, 3 H), 2.85 (s, 3 20 H), 2,97 - 3.08 (m, 1 H), 3.32 (s, 1 H), 4.45 (d, J=5.1 Hz, 2 H), 4.51 (d, J=6.6 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.92 (d, J=7.3 Hz, 1 H), 7.13 - 7.21 (m, 1 H), 7.22 - 7.30 (m, 2 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.20 (t, J=6.2 Hz, 1 H). Example 184 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4 25 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide HO 0 N N N< > NH 0 N The title compound was prepared in a similar manner to N-(3-ethoxybenzyl)-6-methyl-4-(2 (((trans)-4-(m ethylsulfonamido)cyclohexyl)m ethyl)-2H-tetrazol-5-yl)picolinamide (Example 180) by reaction with 2-(3-(aminomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of 30 N-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2 272 WO 2009/016498 PCT/IB2008/002046 methylpyrimidine-4-carboxamide, Example 13) to afford 10.6 mg. 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.08 - 1.27 (m, 5 H), 1.61 (d, J=10.3 Hz, 2 H), 1.89 (d, J=9.5 Hz, 2 H), 2.51 (s, 1 H), 2.65 (s, 3 H), 2.86 (s, 3 H), 3.03 (s, 1 H), 3.67 (t, J=4.8 Hz, 2 H), 3,93 (t, J=5.1 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.79 (d, J=7.3 Hz, 1 H), 6.86 - 6.95 (m, 3 H), 7.20 (t, J=8.1 Hz, 1 H), 8.05 (s, 1 5 H), 8.41 (s, 1 H), 9.19 (t, J=6.2 Hz, 1 H). Example 185 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F N NH
NH
2 0 N 10 Step 1: Preparation of N-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide 0 N N N NH F H NN Tetrahydrofuran (2 mL) and 4-fluoro-3-methylbenzylamine (3.5 g) was added to methyl 6 methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3 methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, 15 Example 153) (2.69 g), The resultant slurry was treated with N,N-dimethylacetamide (2 mL) and heated to 90 *C. After 3 h, the mixture was allowed to cool to room temperature, treated with 1N hydrochloric acid, diluted with water and filtered. The crude product was triturated with methanol, (50 mL) to provided the title compound as a solid (2.06 g, 51%): MS(ES+) m/z 327 (M+H); IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.18 (d, J=1.6 Hz, 3 H), 2.65 (s, 3 H), 4.45 (d, J=6.2 Hz, 2 H), 7.05 (t, 1 H), 20 7.13 - 7.20 (m, 1 H), 7.22 (d, J=7.5 Hz, 1 H), 8.06 (d, J=1.3 Hz, 1 H), 8.45 (d, J=1.1 Hz, 1 H), 9.27 (t, J=6.3 Hz, 1 H). 273 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of tert-butyl (trans)-4-((5-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate F N N H N ~ N'11 NH
N
0 0 N To N-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (1.95 g) was added 5 tert-butyl-trans-(4-hydroxymethyl)cyclohexylcarbamate (1.65 g), polymer supported triphenyiphosphine (7.00 g, Argonaut, 2.15 mmol/g) and anhydrous THF (60 mL). The stirred mixture was cooled in an ice-water bath and treated with di-tert-butyl azodicarboxylate (2.76 g). The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (40% ethyl acetate/hexanes) to afford the title compound as a white, crystalline solid (2.00 g, 62%): MS(ES+) 538 (M+H); 1 H NMR 10 (400 MHz, CDC1 3 ) 6 ppm 1.02 - 1.30 (m, 4 H), 1.42 (s, 9 H), 1.56 - 1.65 (m, 1 H), 1.71 (d, J=13.2 Hz, 2 H), 2.00 - 2.12 (m, 3 H), 2.26 (d, J=1.9 Hz, 3 H), 2.63 (s, 3 H), 4.37 (s, 1 H), 4.52 (d, J=7.3 Hz, 2 H), 4,61 (d, J=6.2 Hz, 2 H), 6.96 (t, 1 H), 7.11 - 7.23 (m, 2 H), 8.04 (d, J=1.1 Hz, 1 H), 8.40 (t, 1 H), 8.71 (s, 1 H). Step 3: Preparation of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H 15 tetrazol-5-yl)-6-methylpicolinamide F N - N N N I NH
NH
2 0 N
ON-
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (trans)-4-((5-(2-((4-fluoro-3 methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate (849.5 mg, 1.58 mmol) in dichloromethane (5 mL), and the mixture was stirred for 30 minutes. The reaction 20 mixture was concentrated under a stream of nitrogen. The residue was dissolved in dichloromethane and neutralized with MP-carbonate resin, The mixture was filtered, washed with dichloromethane followed by methanol, and concentrated under a stream of nitrogen to afford the title compound (781 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.625 min., m/z 438 (M+H). Example 186 25 N-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide 274 WO 2009/016498 PCT/IB2008/002046 F N_ N N NH/N NH N OFN H O Triethylamine (0.071 mL, 0.513 mmol) and methane sulfonyl chloride (0.020 mL, 0.257 mmo!) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 185) (75.0 mg, 0.171 mmol) in 5 tetrahydrofuran (2 mL). The mixture was stirred for approximately 30 min at room temperature and was then concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (29 mg, 33%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.365 min., m/z 516 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.91 - 1.35 (m, 4 H), 1.49 - 1.68 (m, 2 H), 1.75 - 2.02 (m, 3 H), 2.19 (s, 3 10 H), 2.65 (s, 3 H), 2.85 (s, 3 H), 2.94 - 3.13 (m, 1 H), 4.45 (d, J=6.6 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.88 - 6.97 (m, 1 H), 6.99 - 7.09 (m, 1 H), 7.12 - 7.21 (m, 1 H), 7.21 - 7.27 (m, 1 H), 8.00 - 8.08 (m, 1 H), 8.35 - 8.45 (m, 1 H), 9.14 - 9.25 (m, 1 H). Example 187 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 15 methylpicolinamide F N' NH NN N / \ H O N~ Acetic anhydride (0.065 mL, 0.687 mmol) and 4-(dimethylamino)pyridine Si bound (1,659 g, 1.145 mmol, 0.69 mmol/g loading) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in 20 Example 185) (100.0 mg, 0.229 mmol) in dichloromethane (2 mL). The mixture was agitated overnight at room temperature, filtered, and N,N-dimethylformamide. The filtrate was concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min) to afford the title compound as a solid (33 mg, 30%). LC/MS (5%-100%
CH
3
CN/H
2 0, 10.0 min.): 4.82 min., m/z 480 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 0.95 - 1.29 25 (m), 1.53 - 1.82 (m), 1.90 - 2.04 (m, 1 H), 2.19 (s, 3 H), 3.35 - 3.52 (m, 1 H), 4.46 (d, J=5.9 Hz, 2 H), 4.64 (d, J=6.6 Hz, 2 H), 6.99 - 7.08 (m, 1 H), 7.13 - 7.21 (m, 1 H), 7.21 - 7.28 (m, 1 H), 7.59 - 7.67 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.16 - 9.24 (m, 1 H). 275 WO 2009/016498 PCT/IB2008/002046 Example 188 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F N'N ' NH N H NH 2 0 N 5 O-(7-Azabenzotriazole-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (78.0 mg, 0.205 mmol), 3-(tert-butoxycarbonyl)propanoic acid (32.4 mg, 0.171 mmol), and diisopropylethylamine (0.060 mL, 0.342 mmol) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 185) (100.0 mg, 0.229 mmol) (75.0 mg, 0.171 mmol) in N,N-dimethylformamide (2 mL). The mixture 10 was stirred overnight at room temperature and was then concentrated under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min). The resulting intermediate was dissolved in dichloromethane and trifluoroacetic acid was added. The mixture was stirred for approximately 30 min and then concentrated under a stream of nitrogen. The residue was dissolved in dichloromethane and stirred with MP-carbonate resin for approximately 30 15 minutes. The mixture was filtered and washed with dichloromethane followed by methanol. The filtrate was concentrated under a stream of nitrogen to afford the title compound as a solid (15 mg, 17%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.833 min., m/z 509 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.98 - 1.20 (m, 4 H), 1.49 - 1.65 (m, 2 H), 1.67 - 1.82 (m, 2 H), 1.94 (s, 3 H), 2.06 - 2.14 (m, 2 H), 2.17 (s, 3 H), 2.49 - 2.56 (m, 2 H), 2.60 (s, 3 H), 4.43 (d, J=6.6, Hz, 2 H), 20 4.59 (d, J=6.6 Hz, 2 H), 6.95 - 7.07 (m, 1 H), 7.10 - 7.19 (m), 7.21 (m, 1 H), 7.70 (m, 1 H), 7.96 (s, 1 H), 8.34 (s, 1 H), 9.08 - 9.18 (m, 1 H). Example 189 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(2-methoxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F NH N N O H 0 N 25 The title compound was prepared in a similar manner to N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 188) by reaction with 2-methoxyacetic acid to afford 42.2 mg (48%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min, 95% CH 3 CN, 1.5 min.): 3.356 min., m/z 510 (M+H). 'H NMR (400 MHz, DMSO 30 d,) 6 ppm 0.99 - 1.39 (m, 4 H), 1.51 - 1.81 (m, 4 H), 1.83 - 2.07 (m, 2 H), 2.19 (s, 3 H), 2.65 (s, 3 H), 276 WO 2009/016498 PCT/IB2008/002046 3.43 - 3.63 (m, 2 H), 3.72 (s, 3 H), 4.45 (d, J=6.6 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 6.96 - 7.10 (m, 1 H), 7.12 - 7.21 (m, 1 H), 7.20 - 7.29 (m, 1 H), 7.39 - 7.50 (m, 1 H), 8.05 (s, I H), 8.40 (s, 1 H), 9.13 9.26 (m, 1 H). Example 190 5 2-((trans)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexylamino)-2-oxoethyl acetate F N' N O NH -NN 0 H O N The title compound was prepared in a similar manner to N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 10 188) by reaction with 2-acetoxyacetic acid to afford 49.2 mg (54%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min, 95% CH 3 CN, 1.5 min.): 3.353 min. 538 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.00 - 1.31 (m, 4 H), 1.49 - 1.84 (m, 4 H), 1.87 - 2.01 (m, 1 H), 2.03 (s, 3 H), 2.19 (s, 3 H), 2.65 (s, 3 H), 3.39 - 3.61 (m, 1 H), 4.36 (s, 2 H), 4.45 (d, J=5.9 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 6.96 - 7.10 (m, 1 H), 7.12 - 7.21 (m, 1 H), 7.21 - 7.28 (m, 1 H), 7.71 - 7.84 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 15 9.16 - 9.25 (m, 1 H). Example 191 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F 'N N NH N OH /\ H O N 20 The title compound was prepared in a similar manner to N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 188) by reaction with 2-hydroxyacetic acid to afford 37.5 mg (44%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH3CN, 1.5 min.): 3.080 min., m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d) J ppm 1.04 - 1.42 (m, 4 H), 1.50 - 1.83 (m, 4 H), 1.85 - 2.07 (m, 1 H), 2.19 (s, 3 H), 2.65 (s, 25 3 H), 3.41 - 3.64 (m, 1 H), 3.73 (s, 2 H), 4.45 (d, J=6.6 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 6.97 - 7.11 (m, 1 H), 7.13 - 7.21 (m, 1 H), 7.21 - 7.27 (m, 1 H), 7.32 - 7.43 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.13 - 9.26 (m, 1 H). 277 WO 2009/016498 PCT/IB2008/002046 Example 192 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(3-methoxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide F N I , N 0 NH N H O 0 N 5 The title compound was prepared in a similar manner to N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 188) by reaction with 3-methoxypropanoic acid to afford 39.7 mg (44%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.298 min., m/z 524 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 1.00 - 1.22 (m, 4 H), 1.52 - 1.82 (m, 4 H), 1.87 - 2.03 (m, 1 H), 2.19 (s, 3 H), 2.23 (t, 10 J=6.6 Hz, 2 H), 2.65 (br. s., 6 H), 3.35 - 3.54 (m, 3 H), 4.45 (d, J=6.6 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 6.96 - 7.09 (m, 1 H), 7.11 - 7.20 (m, 1 H), 7.20 - 7.27 (m, 1 H), 7.55 - 7.75 (m, 1 H), 7.97 - 8.09 (m, 1 H), 8.35 - 8.46 (m, 1 H), 9.15 - 9.27 (m, 1 H). Example 193 N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazol 15 5-yl)-6-methylpicolinamide F 'N N NH NN NH 2 H o N The title compound was prepared in a similar manner to N-(4-fluoro-3-methylbenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 188) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 33.7 mg (40%). LC/MS (5%-95% 20 CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.790 min., m/z 495 (M+H). H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.08 - 1.28 (m, 4 H), 1.52 - 1.83 (m, 4 H), 1.89 - 2.04 (m, 1 H), 2.19 (s, 3 H), 2.65 (s, 3 H), 3.01 (s, 2 H), 3.38 - 3.57 (m, 1 H), 4.45 (d, J=5.9 Hz, 1 H), 4.65 (d, J=7.3 Hz, 1 H), 7.00 - 7.09 (m, 1 H), 7.11 - 7.19 (m, 1 H), 7.21 - 7.28 (m, 1 H), 7.51 - 7.62 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.17 - 9.26 (m, 1 H), 25 Example 194 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 278 WO 2009/016498 PCT/IB2008/002046 F Cl N N N "' NH
NH
2 0 N Step 1: Preparation of N-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-vl)picolinamide 0 N'N C N N NH H N 4-Fluoro-3-chlorobenzylamine (3.52 g) was added to a solution of methyl 6-methyl-4-(2H 5 tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (2.20 g) in N,N-dimethylacetamide (4 mL). The mixture was heated to 90 *C for 2 hours. The reaction mixture was allowed to cool, treated with water and filtered. The solids were triturated with methanol (50 mL) overnight to afford the title compound as an off-white solid (2.00 g, 47%). MS(ES+) m/z 347 (M+H). IH 10 NMR (400 MHz, DMSO-d) 6 ppm 2.66 (s, 3 H), 4.49 (d, J=6.4 Hz, 2 H), 7.30 - 7.39 (m, 1 H), 7.53 (d, J=7.8 Hz, 1 H), 8.07 (d, J=1.1 Hz, 1 H), 8.44 (s, 1 H), 9.40 (t, J=6.4 Hz, 1 H). "F NMR (376 MHz, DMSO-d 6 ) 6 ppm -119.66 (q). Step 2: Preparation of tert-butyl (trans)-4-((5-(2-((3-chloro-4-fluorobenzvl)carbamoyl)-6-methylDyridin 4-Vl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate. F Cl N O NH / N NH O H _ 0 N 15 tert-Butyl-trans-(4-hydroxymethyl)cyclohexylcarbamate (1.46 g), polymer supported triphenylphosphine (Argonaut, 2.15 mmol/g, 6.17 g), and anhydrous tetrahydrofuran (55 mL) were added to N-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (1.84 g). The stirred mixture was cooled in an ice-water bath and treated with di-tert-butyl azodicarboxylate (2.45 g). After 20 30 min, the ice bath was removed and the mixture allowed to stir overnight at room temperature. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (40% ethyl acetate/hexanes) to afford the title compound as a yellow, crystalline solid (0.83 g, 28%). MS(ES+) m/z 558 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.02 - 1.29 (m, 4 H), 1.42 (s, 9 H), 1.71 (d, J=12.6 Hz, 2 H), 2.00 - 2.14 (m, 3 H), 2.62 - 2.68 (m, 3 H), 3.31 - 3.50 (m, 1 H), 4.34 - 4.45 (m, 1 25 H), 4.52 (d, J=7.3 Hz, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 7.10 (t, J=8.6 Hz, 1 H), 7,21 - 7.29 (m, 1 H), 7.42 279 WO 2009/016498 PCT/IB2008/002046 (dd, J=7.0, 2.2 Hz, 1 H), 8.06 (d, J=1.1 Hz, 1 H), 8.51 (t, J=6.2 Hz, 1 H), 8.71 (d, J=1.1 Hz, 1 H). 1 9 F NMR (376 MHz, CDCl 3 ) 6 ppm -117.85 (br s). Step 3: Preparation of N-(3-chloro-4-fluorobenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F CI N ' N NH N
NH
2 0 N 5 Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (trans)-4-((5-(2-((3-chloro-4 fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate (199.8 mg, 0.358 mmol) in dichloromethane (5 mL), and the mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated under a stream of nitrogen. The residue was dissolved in 10 dichloromethane and neutralized for approximately 30 min with MP-carbonate resin. The mixture was filtered and washed with dichloromethane and methanol. The filtrate was concentrated under a stream of nitrogen for a quantitative yield. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.687 min., m/z 458 (M+H). Example 195 15 N-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide F CI N Cl - N' NQ NH N' H O o N~ Triethylamine (0.068 mL, 0.492 mmol) and methane sulfonyl chloride (0.019 mL, 0,246 mmol) were added to a solution of N-(3-chloro-4-fluorobenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H 20 tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 194) (75.1 mg, 0.164 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min) to afford the title compound as a solid (45.6 mg, 52%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.384 min., m/z 536 (M+H). 'H NMR (400 MHz, 25 DMSO-d 6 ) 6 ppm 0.98 - 1.31 (m, 4 H), 1.53 - 1.67 (m, 2 H), 1.78 - 2.03 (m, 3 H), 2.66 (s, 3 H), 2.85 (s, 3 H), 2.95 - 3.12 (m, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.64 (d, J=6.6 Hz, 2 H), 6.86 - 6.96 (m, 1 H), 7.26 7.39 (m, 2 H), 7.49 - 7.56 (m, 1 H), 8.02 - 8.10 (m, 1 H), 8.36 - 8.42 (m, 1 H), 9.29 - 9.38 (m, 1 H). 280 WO 2009/016498 PCT/IB2008/002046 Example 196 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F Cl N N N NH N H 0 N 5 Acetic anhydride (0.037 mL, 0.393 mmol) and 4-(dimethylamino)pyridine Si bound (949.0 mg, 0.655 mmol, 0.69 mmol/g loading) were added to a solution of N-(3-chloro-4-fluorobenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 194) (60.0 mg, 0.131 mmol) in dichloromethane (2 mL), and the mixture was agitated overnight at room temperature. The reaction mixture was filtered and washed with N,N 10 dimethylformamide. The filtrate was concentrated under a stream of nitrogen and purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (23 mg, 35%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.93 min., m/z 500 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.94 - 1.27 (m), 1.54 - 1.83 (m), 1.89 - 2.04 (m, 1 H), 2.66 (s, 3 H), 3.28 (s), 3.35 3.52 (m, 1 H), 4.49 (d, J=5.9 Hz, 2 H), 4.64 (d, J=7.3 Hz, 2 H), 7.26 - 7.38 (m, 2 H), 7.46 - 7.57 (m, 1 15 H), 7.59 - 7.67 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.39 (m, 1 H). Example 197 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F ,N CI N ON NH N N /- \H NH 2 0 N 20 0-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (65.0 mg, 0.170 mmol), 3-(tert-butoxycarbonyl)propanoic acid (26.9 mg, 0.142 mmol), and diisopropylethylamine (0.049 mL, 0.284 mmol) were added to a solution of N-(3-chloro-4-fluorobenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 194) (65.0 mg, 0.142 mmol) in N,N-dimethylformamide (2 mL), and the mixture was overnight at room 25 temperature. The reaction mixture was concentrated, treated with trifluoroacetic acid, and purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (24.0 mg, 32%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 3.86 min., m/z 529 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.05 - 1.23 (m, 4 H), 1.53 - 1.81 (m, 4 H), 1.90 - 2.03 (m, 1 H), 2.10 (t, J=6.6 Hz, 2 H), 2.66 (s, 3 H), 2.69 (t, J=6.6 Hz, 2 H), 3.28 (br. s.), 3.40 - 3.53 (m, 1 H), 4.49 (d, J=5.9 Hz, 2 281 WO 2009/016498 PCT/IB2008/002046 H), 4.65 (d, J=6.6 Hz, 2 H), 7.23 - 7.38 (m, 2 H), 7.48 - 7.57 (m, 1 H), 7.66 - 7.75 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.39 (m, 1 H). Example 198 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-(2-methoxyacetamido)cyclohexyl)methyl)-2H 5 tetrazol-5-yI)-6-methylpicolinamide F Ci N' N'0 CNH NN kO H o N The title compound was prepared in a similar manner to N-(3-Chloro-4-fluorobenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)m ethyl)-2H-tetrazol-5-yl)-6-m ethylpicolinam ide (Example 197) by reaction with 2-methoxyacetic acid to afford 35 mg (46%) as a solid. LC/MS (5%-100% 10 CH 3
CN/H
2 0, 10.0 min.): 5.13 min., m/z 530 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.06 - 1.34 (m, 4 H), 1.54 - 1.78 (m, 4 H), 1.86 - 2.05 (m, 1 H), 2.66 (s), 3.23 - 3.33 (m), 3.45 - 3.62 (m, 1 H), 3.72 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 7.29 - 7.39 (m, 2 H), 7.43 - 7.49 (m, 1 H), 7.50 - 7.58 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.37 (m, 1 H). Example 199 15 2-((trans)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carba moyl)-6-methylpyrid in-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexylamino)-2-oxoethyl acetate F N CNH N N O H o N The title compound was prepared in a similar manner to N-(3-Chloro-4-fluorobenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 20 197) by reaction with 2-acetoxyacetic acid to afford 31.2 mg (39%) as a solid. LC/MS (5%-100%
CH
3
CN/H
2 0, 10.0 min.): 5.06 min., m/z 558 (M+H). H NMR (400 MHz, DMSO-d 6 ) J ppm 1.06 - 1.29 (m, 4 H), 1,55 - 1.84 (m, 4 H), 1.89 - 2.01 (m, 1 H), 2.04 (s, 3 H), 2.66 (s, 3 H), 3.41 - 3.59 (m, 1 H), 4.36 (s, 2 H), 4.49 (d, J=5.9 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 7.30 - 7.38 (m, 2 H), 7.50 - 7.55 (m, 1 H), 7.75 - 7.82 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.38 (m, 1 H). 25 Example 200 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 282 WO 2009/016498 PCT/IB2008/002046 F -- ,N..~, Cl N' N CNH N N OH / \ H 0 N The title compound was prepared in a similar manner to N-(3-Chloro-4-fluorobenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 197) by reaction with 2-hydroxyacetic acid to afford 48.2 mg (66%) as a solid. LC/MS (5%-100% 5 CH 3
CN/H
2 0, 10.0 min.): 4.74 min., m/z 516 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.05 - 1.35 (m, 4 H), 1.55 - 1.79 (m, 4 H), 1.88 - 2.03 (m, 1 H), 2.66 (s, 3 H), 3.28 (br. s.), 3.47 - 3.61 (m, 1 H), 3.73 (s, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 4.65 (d, J=6.6 Hz, 2 H), 7.24 - 7.44 (m, 3 H), 7.48 - 7.58 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.27 - 9.41 (m, 1 H). Example 201 10 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-(3-methoxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F CI N' O NH N H 0 0 N The title compound was prepared in a similar manner to N-(3-Chloro-4-fluorobenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 15 197) by reaction with 3-methoxypropanoic acid to afford 49.1 mg (64%) as a solid. LC/MS (5%-100%
CH
3
CN/H
2 0, 10.0 min.): 5,01 min., m/z 544 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.01 - 1.25 (m, 4 H), 1.50 - 1.81 (m, 4 H), 1.86 - 2.05 (m, 1 H), 2.23 (t, J=6.6 Hz, 2 H), 2.66 (s, 3 H), 3.24 - 3.32 (m), 3.47 (t, J=6.2 Hz, 2 H), 4.49 (d, J=5.9 Hz, 2 H), 4.64 (d, J=6.6 Hz, 2 H), 7.29 - 7.39 (m, 2 H), 7.49 - 7.55 (m, 1 H), 7.60 - 7.68 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.38 (m, 1 H). 20 Example 202 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazol 5-yl)-6-methylpicolinamide 283 WO 2009/016498 PCT/IB2008/002046 F C- N~ N'0 NH -N N NH 2 / \ H 0 N The title compound was prepared in a similar manner to N-(3-Chloro-4-fluorobenzyl)-4-(2 (((trans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 197) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 45.6 mg (62%) as a solid. LC/MS 5 (5%-100% CH 3
CN/H
2 0, 10.0 min.): 3.81 min., m/z 515 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.03 - 1.27 (m, 4 H), 1.50 - 1.84 (m, 4 H), 1.89 - 2.05 (m, 1 H), 2.66 (s, 3 H), 3.04 (s), 3.27 (br. s.), 3.41 - 3.57 (m, 1 H), 4.49 (d, J=5.9 Hz, 2 H), 4.65 (d, J=7.3 Hz, 2 H), 7.26 - 7.39 (m, 2 H), 7.50 - 7.55 (m, 1 H), 7.58 - 7.65 (m, 1 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.30 - 9.38 (m, 1 H). Example 203 10 N-(4-Fluoro-3-((2-hydroxyethoxy)methyl)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido) cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide F HO O N -N 0 N NH N \\ H O 0 N N-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in 15 Example 181) (38 mg, 0.059 mmol), potassium carbonate (8.13 mg, 0.59 mmol), and ethanol (5 mL) were combined in a 20 mL scintillation vial with a magnetic stir bar and reflux for 2 hours. The reaction mixture was cooled in an ice bath and ethylene oxide (7.13 mg, 0.162 mmol) was added, The mixture was slowly warmed to room temperature and stirred for 36 hours. The reaction mixture was concentrated and purified by preparative reverse phase preparative HPLC to afford the title compound 20 as a white solid (30.8 mg, 76%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.71 min., m/z 576 (M+H). 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.25 (t, J=6.22 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.44 (d, J=7,32 Hz, 1 H), 7.19 - 7.28 (m, J=6.59 Hz, 1 H), 7.06 (t, 1 H), 6.92 (d, J=7.32 Hz, 1 H), 5.20 (t, J=5.49 Hz, 1 H), 4.64 (d, J=6.59 Hz, 2 H), 4.50 (d, J=5.12 Hz, 3 H), 3.28 (d, J=5.12 Hz, 1 H), 2.97 - 3.11 (m, J=6.59 Hz, 1 H), 2.79 - 2.91 (m, 2 H), 2.65 (s, 2 H), 2.43 - 2.53 (m, 1 H), 1.75 (dd, J=1 11.63, 10.61 Hz, 4 H), 25 1.05 - 1.28 (m, 3 H). Example 204 4-(2-(((trans)-4-Acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-N-((6-hydroxypyridin-2 yl)methyl)-6-methylpicolinamide 284 WO 2009/016498 PCT/IB2008/002046 HO NH N N N NH N H 0 N Step 1: Preparation of 4-(2-((4-acetamidocyclohexvl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinic acid 0 HO N H NN N N _N N N~, 0 Triethylamine (0.95 mL, 6.81 mmol) and acetic anhydride (0.52 mL, 5.45 mmol) were added to 5 a solution of methyl 4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-(3 hydroxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 168) (500 mg, 1.36 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for two days. The reaction mixture was filtered and washed with dichloromethane. The filtrate was 10 concentrated and the residue was dissolved in a mixture of tetrahydrofuran/water (12 mL, 5/1). Lithium hydroxide (131 mg, 5.45 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (165 mg, 34%). MS (ES+) m/z 359 (M+H). 15 Step 2: Preparation 4-(2-(((trans)-4-acetamidocyclohexvl)methyl)-2H-tetrazol-5-yl)-N-((6 hydroxvpvridin-2-yl)methyl)-6-methylpicolinamide 'N ,~ N" NH N H O N N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (254 mg, 0.67 mmol) was added to a mixture of 4-(2-((4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinic acid (160 mg, 0,446 mmol), 6-(aminomethyl)pyridin-2(1H)-one (Bronn, W. R. US 4,555,573, 1985) (191 mg, 0.67 mmol), and triethylamine (0.22 mL, 1.56 mmol) in N,N dimethylformamide (2 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a solid (106 mg, 51%). MS (ES+) m/z 465 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.99 - 1.21, (m, 4 H), 1.58 25 (s, J=9.52 Hz, 2 H), 1.67 - 1.81 (m, 5 H), 1.87 - 2.00 (m, 2 H), 2.66 (s, 3 H), 3.36 - 3.48 (m, 1 H), 4.33 (d, J=5.86 Hz, 2 H), 4.63 (d, J=7.32 Hz, 2 H), 5.98 - 6.10 (m, 1 H), 6.17 (d, J=9.52 Hz, 1 H), 7.24 7.37 (m, 1 H), 7.61 (d, J=8.05 Hz, 1 H), 8.07 (s, 1 H), 8.38 (s, 1 H), 9.24 (t, J=6.95 Hz, 1 H). 285 WO 2009/016498 PCT/IB2008/002046 Example 205 N-(3-(Hydroxymethyl)benzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl) -6 methylpicolinamide HOH HONH N'NN 0 N 5 N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (159 mg, 0.42 mmol) was added to a mixture of 4-(2-((4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-N-((6-hydroxypyridin-2-yl)methyl)-6-methylpicolinamide, Example 204) (50 mg, 0.14 mmol), (3-(aminomethyl)phenyl)methanol (prepared as described in step 1 10 of the synthesis of N-(3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide, Example 183) (29 mg, 0.21 mmol), and triethylamine (0.03 mL, 0.21 mmol) in N,N-dimethylformamide (2 mL), The mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The 15 resulting residue was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a solid (22 mg, 33%). MS (ES+) m/z 478 (M+H). IH NMR (400 MHz, DMSO-d) 6 ppm 1.04 - 1.26 (m, 6 H), 1.56 - 1.67 (m, 2 H), 1.71 - 1.85 (m, 5 H), 1.91 - 2.03 (m, 1 H), 2.67 (s, 3 H), 3.25 - 3.35 (m, 1 H), 4.48 (s, 2 H), 4.54 (d, J=6.59 Hz, 2 H), 4.67 (d, J=7.32 Hz, 2 H), 7.14 - 7.34 (m, 3 H), 7.66 (d, J=7.32 Hz, 1 H), 8.08 (s, 1 H), 8.44 (s, 1 H), 9.22 (t, 20 J=5.86 Hz, 1 H). Example 206 N-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazoI-5-yl) -6 methylpicolinamide HO 0 N N N HNH N 0 N 25 N, N, N', N'-Tetramethyl-O-(1 H-benzotriazol- 1 -yl)uronium hexafluorophosphate (159 mg, 0.42 mmol) was added to a mixture of 4-(2-((4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-N-((6-hydroxypyridin-2-yl)methyl)-6-methylpicolinamide, Example 204) (50 mg, 0.14 mmol), 2-(3-(aminomethyl)phenoxy)ethano (prepared as described in step 30 2 of the synthesis of N-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 13) (35 mg, 0.21 mmol), and triethylamine 286 WO 2009/016498 PCT/IB2008/002046 (0.03 mL, 0.21 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The resulting residue was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title 5 compound as a solid (26 mg, 37%). MS (ES+) m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.04 - 1.24 (m, 5 H), 1.58 - 1.68 (m, 2 H), 1.72 - 1.84 (m, 5 H), 1.92 - 2.05 (m, 2 H), 2.68 (s, 3 H), 3.69 (t, J=5.12 Hz, 2 H), 3.96 (t, J=5.12 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 4.67 (d, J=7.32 Hz, 2 H), 6.82 (d, J=7.32 Hz, 1 H), 6.88 - 6.96 (m, 1 H), 7.23 (t, J=8.05 Hz, 1 H), 7.66 (d, J=7.32 Hz, 1 H), 8.08 (s, 1 H), 8,43 (s, 1 H), 9.22 (t, J=6.59 Hz, 1 H). 10 Example 207 N-(4-Fluoro-3-(hydroxymethyl)benzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazol 5-yi)-6-methylpicolinamide F HO
-
N H 0 N N,N,N',N'-Tetramethyl-O-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (476 mg, 1.26 15 mmol) was added to a mixture of 4-(2-((4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((trans)-4 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-N-((6-hydroxypyridin-2-yl)methyl)-6-methylpicolinamide, Example 204) (150 mg, 0.42 mmol), (5-(aminomethyl)-2-fluorophenyl)methanol (prepared as described in step 1 of the synthesis of N-(4-fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 20 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide, Example 181) (120 mg, 0.63 mmol), and triethylamine (0.15 mL, 1.05 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The resulting residue was taken up in methanol and passed through a carbonate cartridge. The filtrate 25 was concentrated to afford the title compound as a solid (112 mg, 54%). MS (ES+) m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.04 - 1.27 (m, 4 H), 1.55 - 1.68 (m, Hz, 2 H), 1.71 - 1.84 (m, 5 H), 1.91 - 2.06 (m, 2 H), 2.67 (s, 3 H), 3.82 (s, 3 H), 4.51 (d, J=5.86 Hz, 2 H), 4.67 (d, J=7.32 Hz, 2 H), 6.82 - 6.96 (m, 1 H), 7.05 - 7.26 (m, 2 H), 7.65 (d, J=7.32 Hz, 1 H), 8.07 (s, 1 H), 8.43 (s, 1 H), 9.24 (t, J=6.22 Hz, 1 H). 30 Example 208 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 287 WO 2009/016498 PCT/IB2008/002046 O NH NN N HNH N IF-\ H 0 N N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (159 mg, 0.42 mmol) was added to a mixture of 4-(2-((4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((trans)-4 5 acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-N-((6-hydroxypyridin-2-yl)methyl)-6-methylpicolinamide, Example 204) (50 mg, 0.14 mmol), (3-ethoxyphenyl)methanamine (prepared as described in step 2 of the synthesis of N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide, Example 180) (31 mg, 0.21 mmol), and triethylamine (0.03 mL, 0.21 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 18 hours. 10 The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The resulting residue was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a solid (39 mg, 57%). MS (ES+) m/z 492 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.02 - 1.25 (m, 4 H), 1.30 (t, J=6.95 Hz, 3 H), 1.53-1.68(m, 2H), 1.72 - 1.85 (m, 5 H), 1.98 (m, 2 H), 2.68 (s, 3 H), 4.00 15 (q, J=6.83 Hz, 2 H), 4.50 (d, J=6.59 Hz, 2 H), 4.67 (d, J=6.59 Hz, 2 H), 6.77 - 6.83 (m, 1 H), 6.87 6.94 (m, 2 H), 7.17 - 7.26 (m, 8.05 Hz, 1 H), 7.60 - 7.70 (m, 1 H), 8.08 (s, 1 H), 8.43 (s, 1 H), 9.21 (t, J=6.22 Hz, 1 H). Example 209 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinamide -,-N o NN NH
NH
2 o N Step 1: Preparation of tert-butyl (cis)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-vl)-2H tetrazol-2-yl)methvl)cyclohexylcarbamate \0 N NH NH O 0 N 25 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (1.0 g, 3.08 mmol), tert-butyl cis-(4 288 WO 2009/016498 PCT/IB2008/002046 hydroxymethyl)cyclohexyl carbamate (1.41 g, 6.17 mmol), and polymer supported-triphenylphosphine (3.580 g, 7.07 mmol) in anhydrous tetrahydrofuran (60 mL) was cooled to 0 *C in an ice bath and then di-tert-butyl azodicarboxylate (1.42 g, 3.08 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was 5 concentrated. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0) to afford the title compound. Step 2: Preparation of N-(3-methoxvbenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide - ,N.. O N NH
NH
2 O N 10 Trifluoroacetic acid was added to a solution of tert-butyl (cis)-4-((5-(2-((3-methoxybenzyl) carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate in dichloromethane and the mixture was allowed to stir for 30 min at room temperature. The reaction mixture was concentrated. The residue was dissolved in dichloromethane and MP-carbonate resin was added. The mixture was agitated for 1 h, filtered, and washed with dichloromethane and methanol. The 15 filtrate was concentrated to afford the title compound as a solid (1.091 g, 81%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.479 min., m/z 436 (M+H). H NMR (400 MHz, DMSO-d 6 ) J ppm 1.33 - 1.86 (m, 8 H), 2.17 - 2.31 (m, 1 H), 2.65 (s, 3 H), 3.18 - 3.28 (m, 1 H), 3.70 (s, 3 H), 4.48 (d, J=6.4 Hz, 2 H), 4.72 (d, J=7.3 Hz, 2 H), 6.76 - 6.84 (m, 1 H), 6.85 - 6.93 (m, 2 H), 7.17 7.27 (m, 1 H), 7.93 (br. s., 2 H), 8.03 - 8.09 (m, 1 H), 8,41 (s, 1 H), 9.19 - 9.28 (m, 1 H). 20 Example 210 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((cis)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide - ~N NH N' N\ \ H O O N Triethylamine (0.048 mL, 0.345 mmol) and methane sulfonyl chloride (0.013 mL, 0.173 mmol) 25 were added to a solution of N-(3-methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide (prepared as described in (Example 209) (50.1 mg, 0.115 mmol) in tetrahydrofuran (1.5 mL) and the mixture was stirred 2 hours at room temperature. The reaction mixture was concentrated and purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0) to afford the title compound as a solid (33.7 mg, 57%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% 30 CH 3 CN, 1.5 min.): 3.188 min., m/z 514 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.29 - 1.79 (m), 1.99 - 2.22 (m), 2.65 (s, 3 H), 2.87 (s, 3 H), 3.36 - 3.48 (m), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.67 289 WO 2009/016498 PCT/IB2008/002046 (d, J=6.6 Hz, 2 H), 6.73 - 6.84 (m, 1 H), 6.84 - 6.97 (m, 3 H), 7.13 - 7.28 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.12 - 9.25 (m, 1 H). Example 211 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 5 methylpicolinamide N' N N~ 0 NH N / \ H 0 N Acetic anhydride (0.033 mL, 0.345 mmol) and 4-(dimethylamino)pyridine Si bound (833.0 mg, 0.575 mmol, 0.69 mmol/g loading) were added to a solution of N-(3-methoxybenzyl)-4-(2-(((cis)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 10 209) (50.0 mg, 0.115 mmol) in dichloromethane (2 mL) and the mixture was agitated overnight at room temperature. The reaction mixture was filtered, washed with N,N-dimethylformamide, and concentrated, The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0) to afford the title compound as a solid (27.1 mg, 49%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.64 min., m/z 478 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.31 - 1.66 (m), 1.80 (s, 3 H), 2.07 - 2.21 15 (m, 1 H), 2.62 - 2.69 (m, 3 H), 3.23 - 3.31 (m), 3.71 (s, 3 H), 3.74 - 3.82 (m, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.68 (d, J=7.3 Hz, 2 H), 6.76 - 6.82 (m, 1 H), 6.86 - 6.94 (m, 2 H), 7.17 - 7.25 (m, 1 H), 7.60 - 7.68 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.14 - 9.23 (m, 1 H). Example 212 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 20 methylpicolinamide !4N -N 0 NH N H NH 2 0 N O-(7-Azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (52.0 mg, 0.138 mmol), 3-(tert-butoxycarbonyl)propanoic acid (21.6 mg, 0.115 mmol), and diisopropylethylamine (0.040 mL, 0.230 mmol) were added to a solution of N-(3-methoxybenzyl)-4-(2-(((cis)-4 25 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 209) (50.1 mg, 0.115 mmol) in N,N-dimethylformamide (2 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, treated with trifluoroacetic acid, and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0) to afford the title compound as a solid (16.3 mg, 28%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 30 2,665 min., m/z 507 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.27 - 1.69 (m), 2.14 (t, J=6.6 Hz, 2 290 WO 2009/016498 PCT/IB2008/002046 H), 2.18 - 2.27 (m, 1 H), 2.65 (s, 3 H), 2.70 (t, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 3.80 (br. s), 4.49 (d, J=6.6 Hz, 2 H), 4.68 (d, J=7.3 Hz, 2 H), 6.74 - 6.82 (m, 1 H), 6.84 - 6.93 (m, 2 H), 7.14 - 7.25 (m, 1 H), 7.80 7.87 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.13 - 9.23 (m, 1 H). Example 213 5 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide / ~N0 ONH N k1O0 H 0 N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((cis)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 212) by 10 reaction with 2-methoxyacetic acid and afforded 26.8 mg (46%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.151 min., m/z 508 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.22 - 1.75 (m), 2.13 - 2.28 (m), 2.52 (s), 2.65 (s, 3 H), 3.71 (s, 3 H), 3.77 (s), 3.78 3.86 (m), 4.49 (d, J=6.6 Hz, 2 H), 4.76 (d, J=7.3 Hz, 2 H), 6.75 - 6.83 (m, 1 H), 6.86 - 6.94 (m, 2 H), 7.17 - 7.25 (m, 1 H), 7.38 - 7.45 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.15 - 9.24 (m, 1 H). 15 Example 214 2-((cis)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl) cyclohexylamino)-2-oxoethyl acetate !4N NN NH N I "O H 0 N O The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((cis)-4-(3 20 aminopropanamido)cyclohexyl)m ethyl)-2H-tetrazol-5-yl)-6-m ethylpicolinamide (Example 212) by reaction with 2-acetoxyacetic acid and afforded 20.9 mg (34%) as a solid. LC/MS (5%-95%
-CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.163 min., m/z 536 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.27 - 1.71 (m), 2.04 (s, 3 H), 2.11 - 2.26 (m, 1 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 3.74 3.84 (m, 1 H), 4.43 (s, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 4.70 (d, J=7.3 Hz, 2 H), 6.74 - 6.83 (m, 1 H), 6.85 25 - 6.98 (m, 2 H), 7.15 - 7.27 (m, 1 H), 7.70 - 7.82 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.12 - 9.24 (m, 1 H). Example 215 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 291 WO 2009/016498 PCT/IB2008/002046 NH N'NN OH / \ H 0 N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((cis)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 212) by reaction with 2-hydroxyacetic acid and afforded 27.4 mg (48%) as a solid. LC/MS (5%-95% 5 CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.897 min., m/z 494 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.26 - 1.76 (m), 2.14 - 2.29 (m), 2.65 (s, 3 H), 3.71 (s, 3 H), 3.78 (s), 3.80 - 3.90 (m, 1 H), 4.49 (d, J=5.9 Hz, 2 H), 4.76 (d, J=7.3 Hz, 2 H), 6.74 - 6.84 (m, 1 H), 6.84 - 6.97 (m, 2 H), 7.16 7.28 (m, 1 H), 7.34 - 7.46 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.12 - 9.25 (m, 1 H). Example 216 10 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(3-methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide NH N O H0 O N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((cis)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 212) by 15 reaction with 3-methoxypropanoic acid and afforded 23.7 mg (40%) as a solid. LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.111 min., m/z 522 (M+H). 1H NMR (400 MHz, DMSO-de) 6 ppm 1.28 - 1.71 (m), 2.06 - 2.21 (m, 1 H), 2.31 (t, J=6.2 Hz, 2 H), 2.65 (s), 3.49 (t, J=6.6 Hz, 2 H), 3.71 (s), 3.75 - 3.83 (m, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.68 (d, J=7.3 Hz, 2 H), 6.74 - 6.84 (m, 1 H), 6.84 - 6.96 (m, 2 H), 7.13 - 7.30 (m, 1 H), 7.56 - 7.68 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.12 20 9.25 (m, 1 H). Example 217 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide N O NH N NH 2 S\ H 0 N 25 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((cis)-4-(3 aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 212) by 292 WO 2009/016498 PCT/IB2008/002046 reaction with 2-(tert-butoxycarbonyl)acetic acid and afforded 13.6 mg (24%) as a solid. LC/MS (5% 95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.628 min., m/z 493 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.19 - 1.73 (m), 2.10 - 2.25 (m, 1 H), 2.60 - 2.66 (m), 2.65 (s, 3 H), 3.05 (s), 3.28 (s), 3.71 (s, 3 H), 3.76 - 3.88 (m, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.72 (d, J=7.3 Hz, 2 H), 6.73 - 6.84 (m, 1 5 H), 6.85 - 6.95 (m, 2 H), 7.14 - 7.26 (m, 1 H), 7.62 - 7.70 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.13 9.23 (m, 1 H). Example 218 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide O N H N, N N / ~N NH N OH / \ H 0 N 10 A mixture of 2-hydroxy isobutyric acid (19 mg, 0.19 mmol) and 1-hydroxybenzatriazole (25 mg, 0.19 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes. N-(3-Methoxybenzyl)-4 (2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 209) (0.085 g, 0.15 mmol), triethylamine (0.026 mL, 0.19 mmol),and polymer supported 15 carbodiimide (0.18 g, 0.23 mmol) were then added. The mixture was allowed to stir for 18 hours at room temperature and then filtered. The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (20 mg, 25%). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.19 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.29 (d, J=8.05 Hz, 1 H), 7.22 (t, J=8.1 Hz, 1 20 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 5.35 (s, 1 H), 4.77 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.17 - 2.30 (m, 1 H), 1.61 - 1.74 (m, 2 H), 1.42 - 1.55 (m, 4 H), 1.30 1.41 (m, 2 H), 1.22 (s, 6 H). Example 219 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 25 methylpicolinamide F \0- NN O -N NH
NH
2 O N~ 293 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of methyl 4-(2-(((cis)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate 0 0 - N N NH NI I77 \ OX I N NNO A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of 5 the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (0.23 g, 1.1 mmol), tert-butyl cis-(4-hydroxymethyl)cyclohexyl carbamate (0.24 g, 1.1 mmol), and polymer supported-triphenylphosphine (0.70 g, 1.6 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to OC in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.29 g, 1.3 mmol) was added. The reaction was allowed to warm to room 10 temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound. Step 2: Preparation of 4-(2-(((cis)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-vl)-6 methylpicolinic acid 0 HO N N O 15 An aqueous solution of sodium hydroxide (2.5 N, 1.0 mL) was added to a mixture of 4-(2 (((cis)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate in acetonitrile (3 mL), and the mixture was stirred 2 hours, The acetonitrile was removed in vacuo and the aqueous residue was acidified to pH 6 with a 10% aqueous solution of hydrochloric acid. This mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (2 x 20 5mL) followed by brine (5 mL), dried over sodium sulfate, and concentrated to afford the title compound. Step 3: Preparation of tert-butyl (cis)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-vl)methyl)cyclohexylcarbamate F - N N'N A NH/N-\ N -k O NH H 0 N 25 A mixture of 4-(2-(((cis)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid and 1-hydroxybenzatriazole (97 mg, 0.72 mmol) in N,N-dimethylformamide (2 mL) was stirred for 5 minutes. 4-Fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H 294 WO 2009/016498 PCT/IB2008/002046 tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (0.13g, 0.66 mmol), triethylamine (0.10 mL, 0.72 mmol), and polymer supported carbodiimide (0.88 g, 0.98 mmol) were added. The mixture was stirred for 18 hours at room temperature and then was filtered. The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was 5 purified by silica column chromatography (0-50%, ethyl acetate/heptane) to afford the title compound as a beige oil. Step 4: Preparation of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H tetrazol-5-vl)-6-methylpicolinamide F - N O N'' N NH /
NH
2 0 N~ 10 Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl (cis)-4-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate in dichloromethane (5 mL), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated and then triturated with diethyl ether to afford the title compound as a trifluoroacetate salt (0.12 g). LC/MS (5-100% CH 3
CN/H
2 0, 6 min) 5.33 min, m/z 454 (M+H). 15 Example 220 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxy-2 methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-y)-6-methylpicolinamide F O N .. NH N OH H 0 N A mixture of 2-hydroxy isobutyric acid (10 mg, 0.09 mmol) and 1-hydroxybenzatriazole (11 20 mg, 0.08 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes. N-(4-Fluoro-3 methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 219) (0.040 g, 0.07 mmol), triethylamine (0.012 mL, 0.085 mmol), and polymer supported carbodiimide (0.082 g, 0.11 mmol) were added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was washed with water (3 x 5 mL) 25 followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (10 mg, 29%). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.29 (d, J=7.3 Hz, 1 H), 7.05 - 7.20 (m, 2 H), 6.89 (d, J=3.7 Hz, 1 H), 5.35 (s, 1 H), 4.77 (d, J=8.1 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 295 WO 2009/016498 PCT/IB2008/002046 H), 3.80 (s, 3 H), 3.71 (br, s., 1 H), 2.61 - 2.70 (m, 3 H), 2.21 (d, J=3.7 Hz, 1 H), 1.61 - 1.74 (m, 2 H), 1.48 (dd, J=10.3, 3.7 Hz, 3 H), 1.27 - 1.40 (m, 2 H), 1.14 - 1.28 (m, 6 H). Example 221 N-(4-Fuoro-3-methoxybenzyl)-4-(2-(((cis)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-2H 5 tetrazol-5-yl)-6-methylpicolinamide F 0 N'N NH N N OH H 0 N A mixture of 2-acetoxyacetic acid (11 mg, 0.092 mmol) and 1-hydroxybenzatriazole (11 mg, 0.08 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes. N-(4-Fluoro-3 methoxybenzyl)-4-(2-(((cis)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 10 (prepared as described in Example 219) (0.040 g, 0.07 mmol), triethylamine (0.012 mL, 0.085 mmol), and polymer supported carbodiimide (0.082 g, 0.11 mmol) were added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in tetrahydrofuran (2 mL) and stirred with an aqueous solution of sodium hydroxide (2.5 N, 15 0.5 mL) for 2 hours at room temperature. The tetrahydrofuran was removed in vacuo and the aqueous residue was acidified with a 10% aqueous solution of hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue that was purified by reverse phase preparative HPLC to afford the title compound (7.3 mg, 20%). 1 H NMR 20 (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.22 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.39 (d, J=8.8 Hz, 1 H), 7.04 - 7.23 (m, 2 H), 6.89 (d, J=6.6 Hz, 1 H), 5.35 (t, J=5.9 Hz, 1 H), 4.76 (d, J=7.3 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.69 - 3.93 (m, 5 H), 2.65 (s, 3 H), 2.21 (br. s., 1 H), 1.65 (br. s., 2 H), 1.41 - 1.55 (m, 4 H), 1.36 (d, J=8.8 Hz, 2 H), Example 222 25 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((cis)-4-acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F 0 NN NH N H 0 N Triethylamine (0.012 mL, 0.085 mmol) and a solution of acetyl chloride (6.3 mg in 0.5 mL dichloromethane) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((cis)-4 296 WO 2009/016498 PCT/IB2008/002046 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 219) (0.040 g, 0.07 mmol) in 2-methyltetrahydrofuran (2 mL). The reaction mixture was stirred for 1 hour at room temperature and was then concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (11 mg, 31%). 1 H NMR 5 (400 MHz, DMSO-de) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.63 (d, J=7.3 Hz, 1 H), 7.03 - 7.25 (m, 2 H), 6.75 - 6.95 (m, 1 H), 4.68 (d, J=7.3 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.80 (s, 4 H), 2.65 (s, 3 H), 2.06 - 2.24 (m, 1 H), 1.79 (s, 3 H), 1.52 - 1.62 (m, 2 H), 1.31 - 1.52 (m, 6 H). Example 223 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazo1-5-y)-6 10 methylpicolinamide HN
NH
2 -O
-
NN N Step 1: Preparation of rac-tert-butyl (1R*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yI)methyl)cyclohexylcarbamate 0 0 HN HN -O - NaN N 15 A solution of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (500.0 mg, 1.54 mmol) in anhydrous tetrahydrofuran (30 mL) and triphenylphosphine resin (1.790 g, 3.85 mmol, 2.15 mmol/g loading) was added to a vial containing rac-tert-butyl (1 R*,3S*)-3-(hydroxymethyl)cyclohexylcarbamate (707.0 mg, 20 3.08 mmol). The mixture was cooled in an ice bath and di-tert-butylazodicarboxylate (710.0 mg, 3.08 mmol) was added. The reaction mixture was agitated overnight at room temperature and then concentrated. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound. 297 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of rac-N-(3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-aminocyclohexvl)methyl)-2H tetrazol-5-vl)-6-methylpicolinamide O HN
NH
2 -0 - N-N -O N N rac-tert-butyl (1R*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 5 tetrazol-2-yl)methyl)cyclohexylcarbamate obtained in step 1 was dissolved in dichloromethane and trifluoroacetic acid and stirred for approximately 30 minutes. The mixture was concentrated and the residue was dissolved in dichloromethane. MP-carbonate resin was added to the solution and the mixture was agitated for approximately 1 hour. The mixture was filtered and the resin was washed with dichloromethane and methanol. The filtrate was concentrated under a stream of nitrogen and 10 dried under high vacuum overnight to afford the title compound as a solid (456 mg, 68%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.531 min., m/z 436 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.86 - 1.99 (m, 8 H), 2.04 - 2.24 (m, 1 H), 2.66 (s, 3 H), 2.91 - 3.11 (m, 1 H), 3.71 (s, 3 H), 4.48 (d, J=6.44 Hz, 2 H), 4.65 - 4.88 (m, 2 H), 6.74 - 6.83 (m, 1 H), 6.86 - 6.93 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.86 (br. s., 2 H), 8.00 - 8.11 (m, 1 H), 8.41 (s, 1 H), 9.19 - 9.30 (m, 1 H). 15 Example 224 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide
-
0 0 SHN HN NH 2 -0 - N.-N N 0-(7-Azabenzotriazole-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (52.0 mg, 20 0.138 mmol), 3-(tert-butoxycarbonyl)propanoic acid (21.6 mg, 0.115 mmol), and diisopropylethylamine (0.040 mL, 0.230 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 223) (50.1 mg, 0.115 mmol) in dimethylformamide (2 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase 25 preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min). The resulting intermediate was added to a mixture of dichloromethane and trifluoroacetic acid and stirred approximately 30 minutes. The mixture was concentrated and the residue was dissolved in dichloromethane. MP-carbonate resin was added and the mixture was agitated for approximately 30 minutes. The mixture was filtered and the resin was washed with dichloromethane and methanol. The filtrate was concentrated and dried overnight under 30 high vacuum to afford the title compound as a solid (19.1 mg, 33%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.669 min., m/z 507 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.83 - 1.79 (m), 2.01 - 2.19 (m), 2.65 (s, 3 H), 3.51 (s), 3.71 (s, 3 H), 4.49 (d, J=6.59 Hz, 2 H), 4.68 (m, 298 WO 2009/016498 PCT/IB2008/002046 2 H), 6.76 - 6.83 (m, 1 H), 6.86 - 6.94 (m, 2 H), 7.18 - 7.26 (m, 1 H), 7.69 - 7.77 (m, 1 H), 8,05 (s, 1 H), 8.40 (s, 1 H), 9.13 - 9.24 (m, 1 H). Example 225 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 5 methylpicolinamide HN HN kO -O - NaN N Acetic anhydride (0.033 mL, 0.345 mmol) and 4-(dimethylamino)pyridine Si bound (833.0 mg, 0.575 mmol, 0.69 mmol/g loading) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2 (((1S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazo-5-yl)-6-methylpicolinamide (prepared as described 10 in Example 223) (50.0 mg, 0.115 mmol) in dichloromethane (2 mL). The mixture was agitated overnight at room temperature. The reaction mixture was filtered, and the resin was washed with dimethylformamide. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (28.0 mg, 51%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.61 min., m/z 478 (M+H). 'H NMR (400 MHz, 15 DMSO-d 6 ) 6 ppm 0.83 - 1.82 (m), 2.01 - 2.18 (m, 1 H), 3.40 - 3.61 (m, 1 H), 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.61 - 4.75 (m), 6.76 - 6.83 (m, 1 H), 6.86 - 6.93 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.63 7.71 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.14 - 9.23 (m, 1 H). Example 226 N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocycohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinamide 0 HN HN 'O N N
N
rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 225) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min). The first eluting enantiomer was 25 isolated to provide 22 mg (8%) of the title compound. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.6 Hz, 1 H), 8.42 (s, 1 H), 8.07 (s, 1 H), 7.68 (d, J=7.3 Hz, 1 H), 7.23 (t, J=8.1 Hz, 1 H), 6.92 (br. s., 2 H), 6.81 (d, J=8.8 Hz, 1 H), 4.62 - 4.78 (m, 2 H), 4.51 (d, J=5.9 Hz, 2 H), 3.73 (s, 3 H), 3.42 - 3.57 (m, 1 H), 2.67 (s, 3 H), 2.53 (s, 1 H), 2.11 (br. s., 1 H), 1.64 - 1.80 (m, 5 H), 1.59 (d, J=1 1.7 Hz, 1 H), 1.20 - 1.34 (m, 1 H), 0.82 - 1.09 (m, 3 H). 299 WO 2009/016498 PCT/IB2008/002046 Example 227 N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide HN HN'O -0 - Nz N N N- N 5 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 225) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min). The second eluting enantiomer was isolated to provide 23 mg (9%) of the title compound. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.66 (d, J=7.3 Hz, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. 10 s., 2 H), 6.80 (d, J=7.3 Hz, 1 H), 4.62 - 4.77 (m, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 3.41 - 3.55 (m, 1 H), 2.60 - 2.73 (m, 3 H), 2.51 (s, 1 H), 2.07 (d, J=19.76 Hz, 1 H), 1.64 - 1.81 (m, 5 H), 1.55 (br. s., 1 H), 1.19 - 1.36 (m, 2 H), 0.80 - 1.08 (m, 2 H). Example 228 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H 15 tetrazol-5-yl)-6-methylpicolinamide -- 0 0 N ON HN OK -0
-
N N N The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 S,3R*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 224) by reaction with 2-methoxyacetic acid and afforded 33.9 mg (58%) as a solid. LC/MS 20 (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.169 min., m/z 508 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.81 - 1.80 (m), 2.03 - 2.20 (m), 2.65 (s, 3 H), 3.50 - 3.66 (m, 1 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.59 - 4.77 (m, 2 H), 6.74 - 6.83 (m, 1 H), 6.86 - 6.94 (m, 2 H), 7.17 - 7.25 (m, 1 H), 7.51 - 7.58 (m, 1 H), 8.06 (s, 1 H), 8.41 (s, 1 H), 9.13 - 9.26 (m, 1 H). Example 229 25 rac-2-((1 R*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2 yl)methyl)cyclohexylamino)-2-oxoethyl acetate -- 0 0 - HN HN O0. -0 - NN N N -N0 NN0 300 WO 2009/016498 PCT/IB2008/002046 The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 S*,3R*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 224) by reaction with 2-acetoxyacetic acid and afforded 32.7 mg (53%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.174 min., m/z 536 (M+H). 'H NMR (400 5 MHz, DMSO-d 6 ) 5 ppm 0.85 - 1.80 (m), 2.03 (s, 3 H), 2.06 - 2.24 (m, 1 H), 2.65 (s, 3 H), 3.46 - 3.64 (m, 1 H), 3.71 (s, 3 H), 4.34 (s, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 4.69 (d, J=5.9 Hz, 2 H), 6.74 - 6.84 (m, 1 H), 6.86 - 6.93 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.76 - 7.85 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.14 9.25 (m, 1 H). Example 230 10 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide
-
0 0 HN HN OH -O -- NN N The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 S*,3R*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 15 (Example 224) by reaction with 2-hydroxyacetic acid and afforded 32.1 mg (57%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.902 min., m/z 493 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.82 - 1.77 (m), 1.99 - 2.20 (m, 1 H), 2.52 (s), 2.65 (s, 3 H), 3.27 - 3.39 (m), 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.57 - 4.77 (m, 2 H), 5.23 - 5.37 (m), 6.74 - 6.82 (m, 1 H), 6.86 6.94 (m, 2 H), 7.17 - 7.25 (m, 1 H), 7.39 - 7.48 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.11 - 9.24 (m, 1 20 H). Example 231 N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 0 0 HN HN OH -0 N NN N- 25 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 230) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min). The first eluting enantiomer was isolated to provide 23 mg (10%) of the title compound. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.43 (d, J=8.1 Hz, 1 H), 7.22 (t, J=8.1 Hz, 1 30 H), 6.90 (br. s., 2 H), 6.80 (d, J=7.3 Hz, 1 H), 5.28 (t, J=5.5 Hz, 1 H), 4.68 (dd, J=6.2, 3.3 Hz, 2 H), 301 WO 2009/016498 PCT/IB2008/002046 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 3.59 (d, J=13.9 Hz, 1 H), 2.65 (s, 3 H), 2.51 (s, 1 H), 2.11 (br. s., 1 H), 1.63 (dd, J=34.8, 20.1 Hz, 4 H), 0.90 - 1.35 (m, 5 H). Example 232 N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5 5 yi)-6-methylpicolinamide 0 0 HN HN OH -O - N N N rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 230) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min). The second 10 eluting enantiomer was isolated to provide 21 mg (10%) of the title compound. IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.43 (d, J=8.1 Hz, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 5.28 (t, J=5.9 Hz, 1 H), 4.63 - 4.76 (m, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 3.60 (d, J= 11.0 Hz, 1 H), 2.65 (s, 3 H), 2.51 (s, 1 H), 2.11 (br. s., 1 H), 1.54 - 1.78 (m, 4 H), 0.84 - 1.37 (m, 5 H). 15 Example 233 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide F O - HN
NH
2 -0 - NzN N 20 N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (1.00 g, 2.64 mmol), t butyl cis-(3-hydroxymethyl)cyclohexylcarbamate (0.73 g, 3.2 mmol), and polymer supported triphenylphosphine (1.76 g, 4.0 mmol) were suspended in anhydrous tetrahydrofuran (50 mL). The 25 mixture was cooled to O *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.73 g, 3.2 mmol) was added. The reaction mixture was allowed to warm to room temperature while stirring over 15 hours. The mixture was filtered and the filtrate was concentrated. The crude residue was purified on silica (20 g, 0-2% methanol/dichloromethane) to afford the protected amine. The intermediate was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. 30 After 2 hours at room temperature, the reaction mixture was diluted with dichloromethane (10 mL) and neutralized with an aqueous solution of sodium hydroxide (2.5 N) for pH 7. The organic layer was 302 WO 2009/016498 PCT/IB2008/002046 separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a beige oil (689 mg, 58%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 3.90-4.15 min, m/z 454 (M+H). Example 234 rac-2-((1 R*,3S*)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 5 tetrazol-2-yl)methyl)cyclohexylamino)-2-oxoethyl acetate F 0 0 F- HN - N HN O -0 - N N NN 0 NN rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide (prepared as described in Example 233) (1.00 g, 2.20 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.19 mL, 2.6 mmol) and a solution of acetoxy acetyl chloride 10 (336 mg) in dichloromethane (1.0 mL) was added. The mixture was stirred for 4 hours at room temperature and was then concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (190 mg). Example 235 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl) 15 2H-tetrazol-5-yi)-6-methylpicolinamide F - HN O HN OH -O
-
NaN N rac-2-((1 R*,3S*)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexylamino)-2-oxoethyl acetate (190 mg) was dissolved in acetonitrile ( 10 mL). An aqueous solution of sodium hydroxide (2.5 N, 4.0 mL) was added and the mixture was 20 stirred for 2 hours, The reaction mixture was concentrated and the aqueous residue was acidified to pH 7 with a 10% solution of hydrochloric acid in water. The neutralized mixture was extracted with ethyl acetate (3 x 1OmL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, and filtered, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound (150 mg). MS (ES+) m/z 512 (M+H). 25 Example 236 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 303 WO 2009/016498 PCT/IB2008/002046 IF 0 FHN HN OH -O
-
NzN N NN rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 235) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% 5 methanol, 70 mL/min). The first eluting enantiomer was isolated to provide 120 mg (21%) of the title compound. 1H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.42 (d, J=8.1 Hz, 1 H), 7.05 - 7.20 (m, 2 H), 6.88 (d, J=8.1 Hz, 1 H), 5.27 (t, J=5.9 Hz, 1 H), 4.59 4.72 (m, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.77 - 3.84 (m, 3 H), 3.71 (d, J=5.1 Hz, 2 H), 3.53 - 3.64 (m, 1 H), 2.65 (s, 3 H), 2.51 (s, 1 H), 2.06 - 2.19 (m, 1 H), 1.49 - 1.75 (m, 3 H), 0.88 - 1.33 (m, 4 H). 10 Example 237 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(2-hydroxyacetamido)cyclohexy)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide F -- 00 - HN HN OH N rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2 15 hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 235) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min). The second eluting enantiomer was isolated to provide 107 mg (19%) of the title compound. 'H NMR (400 MHz, DMSO-d) J ppm 9.20 (t, J=5.9 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.42 (d, J=8.8 Hz, 1 H), 7.05 - 7.22 (m, 2 H), 6.89 (br. s., 1 H), 5.27 (t, J=5.9 Hz, 1 H), 4.68 (d, 20 J=2.9 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.80 (s, 3 H), 3.71 (d, J=5.1 Hz, 2 H), 3.60 (d, J=1 1.7 Hz, 1 H), 2.65 (s, 3 H), 2.51 (s, 1 H), 2.11 (br. s., 1 H), 1.59 (d, J=20.5 Hz, 3 H), 0.84 - 1.36 (m, 4 H). Example 238 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S,3R*)-3-(3-methoxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F-\ \ 0 0 HN H O --O - NaN - 0 N N i N-N "w 25 The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 S*,3R*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 304 WO 2009/016498 PCT/IB2008/002046 (Example 224) by reaction with 3 -methoxypropanoic acid and afforded 35.2 mg (59%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.115 min., m/z 522 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 0.84 - 1.79 (m), 2.01 - 2.17 (m, 1 H), 2.22 (t, J=6.6 Hz, 2 H), 2.65 (s, 3 H), 3.37 - 3.60 (m), 3.71 (s, 3 H), 4.49 (d, J=5.9 Hz, 2 H), 4.61 - 4.77 (m, 2 H), 6.76 - 6.83 (m, 1 H), 6.87 5 6.93 (m, 2 H), 7.18 - 7.25 (m, 1 H), 7.64 - 7.72 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.14 - 9.22 (m, 1 H). Example 239 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 4 0 N HN NH 2 N\ 10 The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 S*, 3 R*)-3-( 3 -aminopropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 224) by reaction with 2-(tert-butoxycarbonyl)acetic acid and afforded 23.0 mg (41%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.634min., m/z 493 (M+H). 1 H 15 NMR (400 MHz, DMSO-d) 6 ppm 0.80 - 1.83 (m), 2.02 - 2.21 (m), 2.65 (s, 3 H), 2.98 (s, 1 H), 3.45 3.61 (m, 1 H), 3,71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.61 - 4.73 (m, 2 H), 6.75 - 6.83 (m, 1 H), 6.86 6.94 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.54 - 7.62 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.13 - 9.25 (m, I H). Example 240 20 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 S*,3R*)-3-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide 0 O\ HN HN -O - N 0 N Triethylamine (0.048 mL, 0.345 mmol) and methane sulfonyl chloride (0.013 mL, 0.173 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-aminocyclohexyl)methyl)-2H 25 tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 223) (50.1 mg, 0.115 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 2 hours at room temperature, The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min) to afford the title compound as a solid (26.0 mg, 44%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.188 min., m/z 514 (M+H). 'H NMR (400 MHz, 30 DMSO-d 6 ) 6 ppm 9.12 - 9.24 (m, 1 H), 8.41 (s, 1 H),8.05 (s, 1 H), 7.16 - 7.26 (m, 1 H), 6.95 - 7.03 (m, 1 H), 6.86 - 6.93 (m, 2 H), 6.75 - 6.83 (m, 1 H), 4.68 (d, J=6.6 Hz, 2 H), 4.49 (d, J=5.9 Hz, 2 H), 3.71 305 WO 2009/016498 PCT/IB2008/002046 (s, 3 H), 2.85 (s, 3 H), 2.65 (s, 3 H), 2.03 - 2.20 (m), 1.81 - 1.92 (m), 1.63 - 1.74 (m), 1.43 - 1.58 (m), 0.82 - 1.37 (m). Example 241 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 5 methylpicolinamide 0 - HN
NH
2 -O N N N Step 1: Preparation of rac-tert-butyl (1 R*,3R*)-3-((5-(2-((3-methoxvbenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylcarbamate O0 0 - HN H N " 0 -0 - N N N 10 A solution of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (500.0 mg, 1.54 mmol) in anhydrous tetrahydrofuran (30 mL) and triphenylphosphine resin (1.790 g, 3.85 mmol, 2.15 mmol/g loading) was added to a vial containing rac-tert-butyl (1 R*,3R*)-3-(hydroxymethyl)cyclohexylcarbamate (707.0 mg, 15 3.08 mmol). The mixture was cooled in an ice bath and di-tert-butylazodicarboxylate (710.0 mg, 3.08 mmol) was added. The reaction mixture was agitated overnight at room temperature and then concentrated. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound. Step 2: Preparation of rac-N-(3-methoxvbenzvl)-4-(2-(((1R*,3R*)-3-aminocyclohexvl)methyl)-2H 20 tetrazol-5-yl)-6-methylpicolinamide O HN
NH
2 N\ rac-tert-butyl (1R*,3R*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexylcarbamate obtained in step 1 was dissolved in dichloromethane and trifluoroacetic acid and stirred for approximately 30 minutes. The mixture was concentrated and the 25 residue was dissolved in dichloromethane. MP-carbonate resin was added to the solution and the mixture was agitated for approximately 1 hour. The mixture was filtered and the resin was washed 306 WO 2009/016498 PCT/IB2008/002046 with dichloromethane and methanol. The filtrate was concentrated under a stream of nitrogen and dried under high vacuum overnight to afford the title compound as a solid (460 mg, 68%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.514 min., m/z 436 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 - 9.29 (m, 1 H), 8.41 (s, 1 H), 8.05 - 8.08 (m, 1 H), 7.93 (br. s., 2 H), 7.17 5 - 7.26 (m, 1 H), 6.85 - 6.94 (m, 2 H), 6.75 - 6.83 (m, 1 H), 4.68 - 4.86 (m, 2 H), 4.48 (d, J=6.4 Hz, 2 H), 3.70 (s, 3 H), 3.37 - 3.49 (m, 1 H), 2.66 (s, 3 H), 2.45 - 2.56 (m, 1 H), 1.12 - 1.78 (m). Example 242 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 0 0 HN HN k -O - NzN NN 10 0-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (52.0 mg, 0.138 mmol), 2-methoxyacetic acid (10.4 mg, 0.115 mmol), and diisopropylethylamine (0.040 mL, 0.230 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1R*,3R*)-3 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 15 241) (50.1 mg, 0.115 mmol) in N,N-dimethylformamide (2 mL). The mixture was allowed to stir at room temperature overnight and was then concentrated. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (31.9 mg, 55%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.196 min., m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.05 - 9.24 (m, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.41 - 7.50 (m, 1 20 H), 7.16 - 7.26 (m, 1 H), 6.86 - 6.93 (m, 2 H), 6.76 - 6.84 (m, 1 H), 4.70 (d, J=7.32 Hz, 2 H), 4.49 (d, J=5.86 Hz, 2 H), 4.01 (br. s.), 3.76 (s, 3 H), 3.71 (s, 3 H), 2.62 - 2.70 (s, 3 H), 2.32 - 2.45 (m, 1 H), 1.04 - 1.74 (m). Example 243 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 25 methylpicolinamide - HN HN 'O -O N N Acetic anhydride (0.033 mL, 0.345 mmol) and 4-(dimethylamino)pyridine Si bound (833.0 mg, 0.575 mmol, 0.69 mmol/g loading) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2 (((1R*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described 30 in Example 241) (50.0 mg, 0.115 mmol) in dichloromethane (2 mL). The mixture was agitated overnight and then filtered. The filtrate was concentrated and the residue was purified by reverse 307 WO 2009/016498 PCT/IB2008/002046 phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound (30.0 mg, 55%). LC/MS (5%-100% CH 3
CN/H
2 0, 10.0 min.): 4.57 min., m/z 478 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.14 - 9.23 (m, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.65 - 7.73 (m, 1 H), 7.18 - 7.26 (m, 1 H), 6.86 - 6.94 (m, 2 H), 6.75 - 6.83 (m, 1 H), 4.66 (d, J=7.32 Hz, 2 H), 4.49 (d, J=5.86 Hz, 2 H), 3.92 - 4.02 (m, 5 1 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 3.28 (s), 2.32 - 2.45 (m, 1 H), 1.78 (s, 3 H), 0.95 - 1.70 (m). Example 244 rac-2-((1 R*,3R*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin4-yl)-2H-tetrazol-2 yl)methyl)cyclohexylamino)-2-oxoethyl acetate 0 0 - HN O HN O -0 - NN N x O 10 The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 *,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 242) by reaction with 2-acetoxyacetic acid to afford 23.7 mg (38%) as a solid. LC/MS (5% 95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.188 min., m/z 536 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.99 - 1.73 (m) 2.01 (s, 3 H), 2.26 - 2.46 (m, 1 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 3.99 15 (br. s.) 4.41 (s, 2 H), 4.49 (d, J=6.59 Hz, 1 H), 4.68 (d, J=7.32 Hz, 2 H), 6.74 - 6.83 (m, 1 H), 6.86 6.95 (m, 2 H), 7.16 - 7.25 (m, 1 H), 7.79 - 7.87 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.14 - 9.23 (m, 1 H). Example 245 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H 20 tetrazol-5-yl)-6-methylpicolinamide - 0 0 HN HN OH -O - N N N The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 R*,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 242) by reaction with 2-hydroxyacetic acid to afford 26.1 mg (46%) as a solid. LC/MS (5% 25 95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.927 min., m/z 494 (M+H). IH NMR (400 MHz, DMSO-de) 6 ppm 1.02 - 1.75 (m) 2.27 - 2.43 (m, 1 H), 2.52 (s, 3 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 3.77 (br. s.) 4.01 (br. s.) 4.49 (d, J=5.86 Hz, 2 H), 4.70 (d, J=7.32 Hz, 2 H), 6.72 - 6.83 (m, 1 H), 6.86 - 6.93 (m, 2 H), 7.17 - 7.26 (m, 1 H), 7.32 - 7.39 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.15 - 9.24 (m, 1 H). 308 WO 2009/016498 PCT/IB2008/002046 Example 246 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-(3-methoxypropanamido)cyclohexyl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide -O 0 - HN H N -0 - N N N 5 The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 R*,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 242) by reaction with 3-methoxypropanoic acid to afford 33.0 mg (55%) as a solid, LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.152 min., m/z 522 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 0.98 - 1.70 (m) 2.30 (t, J=6.22 Hz, 2 H), 2.39 (br. s.) 2.65 (s, 3 H), 3.46 (t, 10 J=6.59 Hz, 2 H), 3.71 (s, 3 H), 3.97 (br. s.) 4.49 (d, J=6.59 Hz, 2 H), 4.66 (d, J=7.32 Hz, 2 H), 6.76 6.83 (m, 1 H), 6,85 - 6.93 (m, 2 H), 7.18 - 7.26 (m, 1 H), 7.65 - 7.73 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.14 - 9.24 (m, 1 H). Example 247 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3-(2-aminoacetamido)cyclohexyl)methyl)-2H-tetrazol 15 5-yl)-6-methylpicolinamide
-
0 0 HN HN NH 2 -O N N The title compound was prepared in a similar manner to rac-N-(3-methoxybenzyl)-4-(2 (((1 R,3R*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 242) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 19.8 mg (41%) as a solid. 20 LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.653 min., m/z 493 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.97 - 1.69 (m) 2.34 (br. s.) 2.65 (s, 3 H), 3.27 (br. s.) 3.71 (s, 3 H), 3.99 (br. s.) 4.49 (d, J=5.86 Hz, 2 H), 4.57 - 4.77 (m, 2 H), 6.72 - 6.84 (m, 1 H), 6.85 - 6.94 (m, 2 H), 7.13 7.27 (m, 1 H), 7.63 - 7.72 (m, 1 H), 8.04 - 8.08 (m, 1 H), 8.39 - 8.47 (m, 1 H), 9.13 - 9.23 (m, 1 H). Example 248 25 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((1R*,3R*)-3-(methylsulfonamido)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide 309 WO 2009/016498 PCT/IB2008/002046 0 0 S HN HN NONI Triethylamine (0.048 mL, 0.345 mmol) and methane sulfonyl chloride (0.013 mL, 0.173 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1R*,3R*)-3-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 241) (50.1 mg, 0.115 mmol) in 5 tetrahydrofuran (1.5 mL). The mixture was stirred for 2 hours at room temperature and was then concentrated. The residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min) to afford the title compound as a solid (29.2 mg, 49%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.198 min., m/z 514 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.09 - 9.25 (m, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.15 - 7.28 (m, 1 H), 6.92 - 6.99 (m, 1 H), 6.86 - 6.93 (m, 2 H), 10 6.73 - 6.83 (m), 4.68 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 3.52 - 3.63 (m), 2.84 (s, 3 H), 2,65 (s, 3 H), 2.32 - 2.46 (m), 1.30 - 1.75 (m), 0.86 - 1.21 (m). Example 249 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide N N NN NH 2 15 Step 1: Preparation of tert-butyl rac-(1R*, 3S*)-3-((5-(2-((-methoxybenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)m ethvl)cvclopentylcarbamate N O -O NaN N N H tert-Butyl (cis)-3-(hydroxymethyl)cyclopentylcarbamate (1.66 g, 6.166 mmol) and polymer 20 supported-triphenylphosphine (5.74 g, 12.3 mmol) was added to a solution of N-(3-methoxybenzyl)-6 methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3 methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) in THF (25 mL) cooled to -20 *C. Di-tert-butylazodicarboxylate (2.84 g, 12.3 mmol) was added and the mixture was stirred at -20 *C for 2 hours. The reaction mixture was allowed to warm 25 and stir overnight. The mixture was filtered and the resin was washed with tetrahydrofuran. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (1.759 g). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.647 min., m/z 522 (M+H). 'H NMR 310 WO 2009/016498 PCT/IB2008/002046 (400 MHz, CDC1 3 ) 6 ppm 1.17 - 1.29 (m, 1 H), 1.37 - 1.46 (m, 9 H), 1.46 - 1.62 (m, 1 H), 1.75 - 1.86 (m, 1 H), 1.86 - 1.96 (m, 1 H), 1.97 - 2.09 (m, 1 H), 2.17 - 2.30 (m, 1 H), 2.57 - 2.73 (m, 3 H), 3.75 3.84 (m, 3 H), 3.96 (br. s., 1 H), 4.54 (d, J=5.6 Hz, 1 H), 4.65 (t, J=7.3 Hz, 3 H), 6.82 (dd, J=8.2, 2.3 Hz, 1 H), 6.88 - 7.01 (m, 1 H), 7.20 - 7.34 (m, 1 H), 8.03 (s, 1 H), 8.42 (t, J=5.8 Hz, 1 H), 8.70 (s, 1 H). 5 Step 2: Preparation of rac-N-(3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-aminocyclopentyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide -0 N-0 N -O N N:'N
N-NNH
2 Trifluoroacetic acid (0.73 mL, 9.84 mmol) was added to a solution of tert-butyl rac-(1R*,3S*)-3 ((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 10 yl)methyl)cyclopentylcarbamate (1.475 g, 1.968 mmol) in dichloromethane (25 mL). The mixture was allowed to stir at room temperature overnight and was then concentrated to afford the title compound as a clear, yellow oil (1.59 g, 100% yield). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.484 min., m/z 422 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 1.62 - 1.75 (m, 2 H), 1.79 - 1.95 (m, 2 H), 2.02 - 2.13 (m, 1 H), 2.21 - 2.32 (m, 1 H), 2.70 (s, 3 H), 3.50 (br. s., 1 H), 3.76 (s, 3 H), 4.62 (d, J=5.9 Hz, 2 H), 4.64 15 4.81 (m, 2 H), 5.28 (s, 2 H), 6.78 - 6.92 (m, 2 H), 6.95 (br. s., 2 H), 7.23 - 7.27 (m, 1 H), 7.72 (br. s., 1 H), 8.15 (s, 1 H), 8.63 (s, 1 H). Example 250 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 S,3R*)-3-(methylsulfonamido)cyclopentyl)methyl) 2H-tetrazol-5-yl)picolinamide H\-0 N O -O N S N N - N \"0 20 H Diisopropylethylamine (0.64 ml, 13.4 mmol) was added to a solution of rac-N-(3 methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 249) (116 mg, 0.275 mmol) in DMF (5.0 mL). After 20 minutes, methanesulfonyl chloride (158 mg, 1.38 mmol) was added and the mixture was allowed to stir 25 overnight. The reaction mixture was concentrated and the residue was purified by preparative reverse phase preparative HPLC to afford the title compound as an oil (62.8 mg, 49%). LC/MS (5%-95%
CH
3
CN/H
2 0, 5 min.) 3.156 min., m/z 500 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm9.19 (t, J=6.22 Hz, 1 H), 8.41 (br. s,, 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.05 Hz, 1 H), 7.09 (d, J=7.32 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.05 Hz, 1 H), 4.77 (d, J=7.32 Hz, 2 H), 4.49 (d, J=5.86 Hz, 2 H), 3.71 (s, 3 H), 2.85 30 (s, 3 H), 2.65 (s, 3 H), 2.01 - 2.13 (m, 2 H), 1.82 - 1.96 (m, 2 H), 1.69 (br. s., 2 H), 1.44 - 1.60 (m, 2 H), 1.23 - 1.37 (m, 2 H). 311 WO 2009/016498 PCT/IB2008/002046 Example 251 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(ethylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 0
S/HN
N O S NN N O H 5 Diisopropylethylamine (0.23 mL, 1.31 mmol) was added to a solution of rac-N-(3 methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 249) (100 mg, 0.131 mmol) in DMF (5.0 mL). After 20 minutes, ethanesufonyl chloride (101 mg, 0.786 mmol) was added and the mixture was allowed to stir overnight. The reaction mixture was concentrated and the residue was purified by preparative reverse 10 phase preparative HPLC to afford the title compound as an oil (25.3 mg, 26%). MS (ES+) m/z 514 (M+H). 'H NMR (400 MHz, methanol-d 4 ) 6 ppm 1.28 (t, J=7.38 Hz, 3 H), 1.34 - 1.45 (m, 1 H), 1.55 1.69 (m, 1 H), 1.79 (d, J=6.71 Hz, 1 H), 1.96 - 2.07 (m, 1 H), 2.14 - 2.24 (m, 1 H), 2.67 (s, 3 H), 3.01 (q, J=7.25 Hz, 2 H), 3.76 (s, 3 H), 4.59 (s, 2 H), 4.74 (d, J=7.52 Hz, 2 H), 6.80 (dd, J=8.06, 2.42 Hz, 1 H), 6.90 - 6.96 (m, 1 H), 7.22 (t, J=8.19 Hz, 1 H), 8.10 (d, J=1.07 Hz, 1 H), 8.57 (s, 1 H). 15 Example 252 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S,3R*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide H\-0 -0 /\ N 0 N O -ON N N H Diisopropylethylamine (128 mg, 1.00 mmol) was added to a solution of rac-N-(3 20 methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 249) (100 mg, 0.131 mmol) in dichloromethane (5 mL). After 20 minutes, acetic anhydride (40 mg, 0.40 mmol) was added. The mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated and the residue was purified by preparative reverse phase preparative HPLC to afford the title compound (58.3 mg, 43%). LC/MS 25 (5%-95% CH 3
CN/H
2 0, 5 min.) 3.071 min., m/z 464 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.22 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.82 (d, J=5.86 Hz, 1 H), 7.21 (t, J=8.05 Hz, 1 H), 6.90 (br. s., 1 H), 6.79 (d, J=7.32 Hz, 2 H), 4.76 (d, J=6.59 Hz, 2 H), 4.49 (d, J=5.86 Hz, 2 H), 3.98 (dd, J=14.64, 7.32 Hz, 1 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.50 - 2.60 (m, 1 H), 2.48 (br. s., 1 H), 1.94 - 2.07 (m, 1 H)1.61 - 1.87 (m, 4 H), 1.37 - 1.56 (m, 2 H), 1.13 - 1.26 (m, 1 H). 312 WO 2009/016498 PCT/IB2008/002046 Example 253 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclopentyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide N HN -O NN OH N - N-N N H 5 Diisopropylethylamine (118 mg, 0.917 mmol) and glycolic acid (19.9 mg, 0.262 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-aminocyclopentyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 249) (100 mg, 0.131 mmol) in N,N-dimethylformamide (5 mL). After 20 min, 0-(1H-benzotriazol-1-yl)-N,N,N',N"-tetramethyluronium tetrafluoroborate (116 mg, 0.360 mmol) was added and the mixture was allowed to stir for 72 hours. 10 The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (30.5 mg, 33%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.958 min., m/z 480 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.19 (t, J=6.22 Hz, 1 H), 8.41 (br. s., 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.05 Hz, 1 H), 6.90 (br. s., 1 H), 6.80 (d, J=8.05 Hz, 1 H), 5.29 (br. s., 1 H), 4.49 (d, J=5.86 Hz, 2 H), 4.03 - 4.18 (m, 1 H), 3.67 - 3.80 (m, 3 H), 2.65 (s, 3 H), 2.50 - 2.62 (m, 1 H), 2.48 (br. 15 s., 1 H), 1.76 - 1.88 (m, 1 H), 1.61 - 1.73 (m, 1 H), 1.53 (d, J=6.59 Hz, 2 H), 1.22 - 1.39 (m, 1 H). Example 254 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(3-hydroxypropanamido)cyclopentyl)methyl)-2H tetrazol-5-yI)-6-methylpicolinamide HN -O N O N I OH - NN N H 20 Diisopropylethylamine (130 mg, 1.01 mmol) and 3-hydroxypropionic acid (26 mg, 0.288 mmol) were added to a solution of rac-N-(3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-aminocyclopentyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 249) (110 mg, 0.144 mmol) in N,N-dimethylformamide (5 mL). After 20 min, 0-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (127 mg, 0.396 mmol) was added and the mixture was allowed to stir for 72 hours. 25 The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (16.1 mg, 15%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.936 min., m/z 494 (M+H). 'H NMR (400 MHz, CD 3 0D) 6 ppm 9.20 (s, 1 H), 8.55 (s, 1 H), 8.10 (s, 1 H), 7.23 (t, J=8.19 Hz, 1 H), 6.91 - 6.96 (m, 2 H), 6.78 - 6.83 (m, 1 H), 4.73 - 4.81 (m, 2 H), 4.59 (s, 2 H), 3.74 3.79 (m, 3 H), 2.66 - 2.70 (m, 3 H), 2.35 (t, J=6.31 Hz, 1 H), 2.13 - 2.22 (m, 1 H), 1.99 (d, J=6.18 Hz, 1 30 H), 1.81 (s, 1 H), 1.51 - 1.67 (m, 2 H), 1.28 - 1.38 (m, 1 H), 313 WO 2009/016498 PCT/IB2008/002046 Example 255 (trans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate F 0 O / \ N' N / IO - NsN 0 5 Step 1: Preparation of N-(4-fluorobenzvl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide 0 N N ,NH I H N A solution of trimethyl aluminum (2M in toluene, 91.25 mL, 0.183 mol) was added to a solution of 4-fluorobenzylamine (22.84 g, 0.183 mol) in anhydrous tetrahydrofuran (400 mL). The reaction mixture was stirred at room temperature for 4 h, at which time the solution was cannulated into a 10 suspension of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide, Example 153) (20.0 g, 0.0913 mol) in anhydrous tetrahydrofuran (400 mL). The reaction mixture was then stirred overnight. The mixture was quenched slowly with methanol and was poured into a 2 L Erlenmeyer containing methanol (500 mL). The mixture was filtered through CeliteTm 15 and concentrated in vacuo. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /tetrahydrofuran, 9/1). The desired fractions were combined and concentrated to afford the title compound (25.4 g, 89%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.33 (t, J= 6.34, 1 H), 8.43 (s, 1 H), 8.05 (s, 1 H), 7.34 (dd, J= 8.5, 2 H), 7.11 (dd, J= 8.9, 2 H), 4.48 (d, J= 6.6, 2 H), 2.64 (s, 3 H). Step 2: Preparation of (trans)-methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyridin-4- yl)-2H 20 tetrazol-2-yl)methyl)cyclohexanecarboxylate F N O N N C Os N N 0 Triethylamine (9.12 g, 0.09 mol)was added to a suspension of the N-(4-fluorobenzyl)-6 methyl-4-(2H-tetrazol-5-yl)picolinamide (12.8 g, 0.04 mol) in acetonitrile (400 mL, anhydrous). trans methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (prepared as described in step 1 of the 25 synthesis of trans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 20) (10.77 g, 0.04 mol) was then added and the reaction mixture was stirred over night at 60 *C. The mixture was concentrated under reduced pressure and the crude product was purified by silica column chromatography 314 WO 2009/016498 PCT/IB2008/002046
(CH
2 Cl 2 /tetrahydrofuran, 9/1). The desired fractions were combined and concentrated to afford the title compound (11 g, 58%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.29 (t, J= 6.34, 1 H), 8.39 (s, 1 H), 8.04 (s, 1 H), 7.36 (m, 2H), 7,11 (m, 2H), 4.64 (d, J= 7.1, 2H), 4.49 (d, J= 6.6, 2H), 3.30 (s, 3H), 2.64 (s, 3H), 2.1 (m, 1H), 1.96 (m, 1H), 1.89 (m, 2H), 1.64 (m, 2H), 1.26 (m, 2H), 1.09 (m, 2H). 5 Example 256 (trans)-4-((5-(2-((4-Fluorobenzyl)carbamoyl)-6-methylpyridin-4-y1)-2H-tetrazo-2 yl)methyl)cyclohexanecarboxylic acid F N N ~ 1 0 H / NN S / N OH - N.N I 0 To a solution of (trans)-methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 10 tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 255) (10 g, 0.021 mol) in tetrahydrofuran (300 mL) was added water (300 mL) and then sodium hydroxide (4.3 g, 0.107 mol). The mixture was stirred vigorously overnight. The tetrahydrofuran was removed under reduced pressure and the resulting alkaline solution was acidified drop wise with 1 M hydrochloric acid until the solution reached pH 5. The mixture was left sitting in a refrigerator overnight. The resulting precipitate 15 was isolated by filtration and washed with water (pH 5). The solid was dried in a vacuum oven overnight to afford the title compound (7.5 g, 77%). Mp 122-124 *C, 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 11.96 (s, 1H), 9.27 (t, J= 6.4, 1H), 8.36 (s, 1H), 8.02 (s, 1 H), 7.33 (dd, J= 8.5, 2H), 7.09 (dd, J= 9.0, 2H), 4.61 (d, J= 6.8, 2H), 4.45 (d, J= 6.3, 2H), 2.61 (s, 3H), 2.07 (m, 1H), 1.93 (m, 1H), 1.85 (d, J= 11, 2H), 1.58 (d, J= 10.8, 2H), 1.25 (m, 2H), 1.07 (m, 2H). 20 Example 257 N-(4-Fluorobenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylcarbamoyl)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide F N 0 O O / \ NN/ N xN -~ NN H 0 - N -N ,, HO "(D 4-(Dimethylamino)pyridine (5.4mg, 0.041mmol) was added to a mixture of (trans)-4-((5-(2-((4 25 fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid (prepared as described in Example 256) (0.20 g, 0.442 mmol), di-(N,N'-succinimidyl)carbonate (0.14g, 0.53 mmol), and triethylamine (0.092 mL, 0.66 mmol) in N,N-dimethylacetamide (2 mL). After 5 minutes, methanesulfonamide (51 mg, 0.53 mmol) was added. The reaction mixture was allowed to stir at room temperature for 24 hours and then purified by reverse phase preparative HPLC to afford 30 the title compound as a solid (0.040 g, 17%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.29 (t, J=6.31 Hz, 315 WO 2009/016498 PCT/IB2008/002046 1 H), 8.39 (s, 1 H), 8.05 (s, 1 H), 7.26 - 7.44 (m, 2 H), 7.02 - 7.18 (m, 2 H), 4.66 (d, J=6.99 Hz, 2 H), 4.48 (d, J=6.45 Hz, 2 H), 3.31 (br. s., 1 H), 2.76 (s, 3 H), 2.61 - 2.69 (m, 4 H), 1.92 - 2.13 (m, 3 H), 1.68 (d, J=12.90 Hz, 2 H), 1.33 - 1.50 (m, 2 H), 1.10 - 1.29 (m, 2 H). Example 258 5 N-(4-Fluorobenzyl)-4-(2-(((trans)-4-(2-hydroxyacetyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F N N _O N-2 N-N 11/,O % OH 0 Oxalyl chloride (3 mL) was added to a solution of (trans)-4-((5-(2-((4-fluorobenzyl)carbamoyl) 6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid (prepared as described in 10 Example 256) (380 mg, 0.84 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was treated with tris(trimethylsiloxy)ethylene (541 mg, 1.85 mmol). The mixture was heated to 90 *C for 3 hours and then was stirred at room temperature for 2 days. The mixture was treated with several drops of 4 N hydrochloric acid until gas stopped evolving. The reaction mixture was purified by reverse phase 15 preparative HPLC. The crude product was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a white solid (79 mg, 20%). LCMS (ES+) m/z 467(M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.02 - 1.40 (m, 4 H), 1.61 - 1.73 (m, J=10.98 Hz, 2 H), 1.91 (s, J=10.98 Hz, 2 H), 1.96 - 2.08 (m, 1 H), 2.20 - 2.32 (m, 1 H), 2.67 (s, 3 H), 3,26 - 3.33 (m, J=2.20 Hz, 1 H), 3.57 (s, 2 H), 4.52 (d, J=5.86 Hz, 2 H), 4.58 - 4.72 (m, 3 H), 7.14 (s, 20 J=8.78, 8.78 Hz, 1 H), 7.39 (dd, J=8.05, 5.86 Hz, 2 H), 8.07 (s, 1 H), 8.42 (s, 1 H), 9.28 (t, J=6.59 Hz, 1 H). Example 259 (trans)-Methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol 25 2-yl)methyl)cyclohexanecarboxylate 0 - \N HO H - N' N N O 0 316 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of (trans)-methyl 4-((3-nitrophenylsulfonyloxy)methyl)cyclohexanecarboxylate S00 DO SO 0 0 2 N 0 A mixture of trans-methyl 4-(hydroxymethyl)cyclohexanecarboxylate (22.0 g, 128 mmol) and 3-nitrobenzene-1-sulfonyl chloride (35.7 g, 161 mmol) in dichloromethane (130 mL) was cooled in an 5 ice bath and triethylamine (23.7 mL, 170 mmol) was added by addition funnel maintaining the temperature below 7*C. The mixture was stirred at this temperature for 1 hour and then quenched with water (1 mL). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was slurried in methanol, filtered, and dried in a vacuum oven 10 to afford the title compound as a white solid (40.66 g, 89%). Step 2: Preparation of methyl 4-(2-(((trans)-4-(methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate \ 0 0
-
N'N N N Os Diisopropylethylamine (20.7 mL, 118.6 mmol) was added by addition funnel to a mixture of 15 (trans)-methyl 4-((3-nitrophenylsulfonyloxy)methyl)cyclohexanecarboxylate (35.9 g, 100.4 mmol) and methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N (3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (20 g, 91.2 mmol) in acetonitrile (120 mL). The mixture was heated at reflux for 7 hours and then was concentrated in vacuo. The residue was suspended in dichloromethane and washed 20 with 1N aqueous sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (heptane/ethyl acetate, 65/35; 50/50) to afford the title compound as a white solid (27 g, 79%). Step 3: Preparation of (trans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzvl)carbamoyl)-6-methylpvridin-4 yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate -N HO H - N 'N N N O 25 0 (3-(Aminomethyl)phenyl)methanol (prepared as described in step 1 of the synthesis of N-(3 (hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide, Example 183) (115 mg, 0,838 mmol) was added to a solution of methyl 4-(2 (((trans)-4-(methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (75 mg, 0.201 317 WO 2009/016498 PCT/IB2008/002046 mmol) in N,N-dimethylformamide (6 mL) and the mixture was heated at 60 0C for 3 days. The reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound as a solid (50 mg, 65%). LC/MS (0%-25% CH 3
CN/H
2 0, 5 min.) 3.010 min., m/z 479 (M+H). IH NMR (400 MHz, methanol-d 4 ) 6 ppm 1.10- 1.24 (m, 2 H), 1.34-1.49 (m, 2 H), 1.74 (dd, J=13.7, 3.0 Hz, 2 H), 1.99 (dd, 5 J=13.8, 3.1 Hz, 2 H), 2.03 - 2.16 (m, 1 H), 2.23 - 2.35 (m, 1 H), 2.65 - 2.71 (m, 3 H), 3.62 (s, 3 H), 3.96 (s, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.74 (s, 2 H), 7.77 (d, J=8.1 Hz, 1 H), 8.03 (dd, J=8.2, 1.5 Hz, 1 H), 8.09 (d, J=1.1 Hz, 1 H), 8.54 (s, 1 H), 8.72 (d, J=1.6 Hz, 1 H). Example 260 (trans)-4-((5-(2-((3-(Hydroxymethyl)benzyl)carbamoyl)-6-methylpyrid in-4-yl)-2H-tetrazol-2 10 yl)methyl)cyclohexanecarboxylic acid 0 N HO H - N / 1 OH NI N':.N 0 (trans)-Methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1.0 mL) and a 4 N aqueous solution of lithium hydroxide (1.0 mL) was added. The mixture was allowed to 15 stir at room temperature overnight. The reaction mixture was concentrated to afford the title compound (16.7 mg, 18%). 1 H NMR (400 MHz, CD 3 0D) 6 ppm 1.12- 1.25 (m, 2 H), 1.35- 1.48 (m, 2 H), 1.70 - 1.78 (m, 2 H), 1.95 - 2.03 (m, 2 H), 2.05 - 2.14 (m, 1 H), 2.25 - 2.35 (m, 1 H), 2.67 (s, 3 H), 3.33 (s, 1 H), 3.62 (s, 3 H), 3.85 (s, 3 H), 4.62 (d, J=7.25 Hz, 2 H), 4.67 (s, 2 H), 6.90 - 6.97 (m, 1 H), 6.97 - 7.08 (m, 2 H), 8.09 (s, 1 H), 8.55 (s, 1 H). 20 Example 261 (trans)-Methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate HON HO H - N N O 1 0 N 0 A mixture of 3-(aminomethyl)phenol (1.01 g, 8.21 mmol) and methyl 4-(2-(((trans)-4 25 (methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (prepared as described in step 2 of the synthesis of (trans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 260) (1.0 g, 2.05 mmol) in methanol (25 mL) was heated at 60 *C for 4 days. The reaction mixture was allowed to cool to room temperature and filtered. The resulting solids were washed with methanol to afford the title 30 compound (770 mg, 80%). MS (ES+) m/z 465 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.06 318 WO 2009/016498 PCT/IB2008/002046 1.22 (m, 2 H), 1.24 - 1.41 (m, 2 H), 1.58 - 1.71 (m, 2 H), 1.85 - 1.95 (m, 2 H), 1.96 - 2.08 (m, 1 H), 2.20 - 2.32 (m, 1 H), 2.67 (s, 3 H), 3.57 (s, 3 H), 4.45 (d, J=6.44 Hz, 2 H), 4.67 (d, J=6.98 Hz, 2 H), 6.62 (d, 1 H), 6.72 - 6.80 (m, 2 H), 7.10 (t, J=7.92 Hz, 1 H), 8.08 (d, J=1.34 Hz, 1 H), 8.43 (s, 1 H), 9.22 (t, J=6.31 Hz, 1 H), 9.32 (s, 1 H). 5 Example 262 (trans)-4-((5-(2-((3-Hydroxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl) cyclohexanecarboxylic acid -N HO H - N'N N ' OH NNa 0 A mixture of (trans)-methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 10 tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 261) (50 mg, 0.11 mmol) and lithium hydroxide (15 mg, 0.65 mmol) in a mixture of tetrahydrofuran/water (5/1, 3 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated and the aqueous residue was treated dropwise with 3N hydrochloric acid until a precipitate formed. The precipitate was taken up in a mixture of dichloromethane and methanol and then passed through an Isolute SPE 103 15 cartridge eluting with dichloromethane/methanol (9/1). The filtrate was concentrated. The residue was washed with water and dried to afford the title compound as a white solid (38 mg, 76%). MS (ES+) m/z 451 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.04 - 1.20 (m, 2 H), 1.21 - 1.38 (m, 2 H), 1.65 (d, J=10.74 Hz, 2 H), 1.90 (d, J=11.01 Hz, 2 H), 1.99 (s, J=7.12, 3.89 Hz, 1 H), 2.08 - 2.20 (m, 1 H), 2.68 (s, 3 H), 4.46 (d, J=6.18 Hz, 2 H), 4.67 (d, J=6.98 Hz, 2 H), 6.58 - 6.66 (m, 1 H), 6.71 - 6.79 (m, 1 20 H), 7.10 (t, J=8.06 Hz, 1 H), 8.08 (d, J=1.34 Hz, 1 H), 8.43 (s, 1 H), 9.15 - 9.27 (m, 1 H), 9.30 (s, 1 H), 12.03 (s, 1 H). Example 263 (trans)-Methyl 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate 0 --O H N'N" N N ON 25 0 A mixture of (trans)-methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 261) (50 mg, 0.11 mmol), 1-bromo-3-methoxypropane (33 mg, 0.22 mmol), potassium carbonate (37 mg, 0.27 mmol), and tetrabutylammonium iodide (4 mg, 0.01 mmol) in N,N-dimethylformamide (2 mL) was heated at 60 30 *C for 18 hours. Additional potassium carbonate (30 mg) was added and heating was continued for 319 WO 2009/016498 PCT/IB2008/002046 18 hours. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as an oil (26 mg, 45%). MS (ES+) m/z 537 (M+H). 'H NMR (400 MHz, CDC 3 ) 6 ppm 1.08 - 1.24 (m, 2 H), 1.37 - 1,55 (m, 2 H), 1.74 - 1.85 (m, 2 H), 1.96 - 2.21 (m, 5 H), 2.22 - 2.35 (m, 1 H), 2.67 (s, 3 H), 3.35 (d, J=1.61 Hz, 3 H), 3.55 (t, J=5.91 Hz, 2 H), 3.67 (s, 3 H), 4.06 (t, J=6.31 Hz, 2 H), 5 4.56 (d, J=6.71 Hz, 2 H), 4.68 (d, J=6.18 Hz, 2 H), 6.77 - 6.89 (m, J=8.32 Hz, 1 H), 6.91 - 7.03 (m, 2 H), 7.21 - 7.33 (m, 1 H), 8.08 (s, 1 H), 8.46 - 8.60 (m, 1 H), 8.76 (s, 1 H) Example 264 (trans)-4-((5-(2-((3-(3-Methoxypropoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid -O O0
-
N -O/ 0 H N N OH 10 0 A mixture of (trans)-methyl 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 263) (25 mg, 0.05 mmol) and lithium hydroxide (5 mg, 0.2 mmol) in a mixture of tetrahydrofuran/water (5/1, 3 mL) was stirred at room temperature for 18 hours. The reaction mixture 15 was acidified with a few drops of 4N hydrochloric acid and purified by reverse phase preparative HPLC to afford the title compound (17 mg, 57%). MS (ES+) m/z 523 (M+H). 'H NMR (400 MHz,
CDC
3 ) 6 ppm 1.11 - 1.25 (m, 2 H), 1.41 - 1.55 (m, 2 H), 1.77-1.86 (m, 2 H), 2.00 - 2.19 (m, 6 H), 2.26 2.37 (m, 1 H), 2.65 (s, 3 H), 3.35 (s, 3 H), 3.46-3.56 (m, 1 H), 3.56 (t, J=6.18 Hz, 2 H), 4.06 (t, J=6.18 Hz, 2 H), 4.56 (d, J=6.98 Hz, 2 H), 4.68 (d, J=5.91 Hz, 2 H), 6.85 (t, J=8.19, 2.28 Hz, 1 H), 6.91 - 7.00 20 (m, 2 H), 8.06 (d, J=1.07 Hz, 1 H), 8.46 (t, J=6.04 Hz, 1 H), 8.74 (s, 1 H). Example 265 (trans)-Methyl 4-((5-(2-((3,4-difluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate F N O FH N N N'O 0 25 A mixture of (3,4-difluorophenyl)methanamine (153 mg, 1.07 mmol) and 4-(2-(((trans)-4 (methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (prepared as described in step 2 of the synthesis of (trans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 260) (100 mg, 0.27 mmol) in tetrahydrofuran (0.5 mL) was heated at 60 *C for 3 days. The reaction mixture was purified 30 by reverse phase preparative HPLC, The fractions containing the desired product were combined and 320 WO 2009/016498 PCT/IB2008/002046 concentrated. The residue was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a white solid (87 mg, 61%). MS (ES+) m/z 485 (M+H). 'H NMR (400 MHz, CDC13) 6 ppm 1.08 - 1.25 (m, 2 H), 1.38 - 1.53 (m, 2 H), 1.79 (dd, J=13.70, 2.95 Hz, 2 H), 1.99 - 2.19 (m, 3 H), 2.22 - 2.35 (m, 1 H), 2.66 (s, 3 H), 3.67 (s, 3 H), 4.56 (d, 5 J=6.98 Hz, 2 H), 4.66 (d, J=6.44 Hz, 2 H), 7.07 - 7.26 (m, 3 H), 8.08 (d, J=1.07 Hz, 1 H), 8.43 - 8.54 (m, 1 H), 8.73 (s, 1 H) Example 266 (trans)-4-((5-(2-((3,4-Difluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazoI-2-yl)methyl) cyclohexanecarboxylic acid F N O F H - N'N N 'O 10 A mixture of (trans)-methyl 4-((5-(2-((3,4-difluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 265) (50 mg, 0.11 mmol)_and lithium hydroxide (8 mg, 0.33 mmol) in a mixture of tetrahydrofuran/water (5/1, 6 mL) was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase 15 preparative HPLC. The fractions containing the desired product were combined and concentrated. The residue was taken up in dichloromethane and saturated sodium chloride solution (2 mL) and passed through a Varian ChemElute column eluting with dichloromethane. The filtrate was concentrated to afford the title compound as a white solid (35 mg, 72%)._MS (ES+) m/z 471 (M+H). 'H NMR (400 MHz, CDC13) 6 ppm 1.11 - 1.29 (m, 2 H), 1.40 - 1.56 (m, 2 H), 1.74 - 1.86 (m, 2 H), 2.02 20 2.22 (m, 3 H), 2.25 - 2.38 (m, 2 H), 2.67 (s, 3 H), 4.56 (d, J=6.98 Hz, 2 H), 4.66 (d, J=6.18 Hz, 2 H), 7.07 - 7.26 (m, 3 H), 8.09 (s, 1 H), 8.44 - 8.63 (m, 1 H), 8.73 (s, 1 H). Example 267 (trans)-Methyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yi)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate 0 -NO O \ H - N N\ / N NN 25 0 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (2.0 g, 6.17 mmol), (trans)-methyl 4 (hydroxymethyl)cyclohexanecarboxylate (2.12 g, 12.33 mmol), and polymer supported 30 triphenylphosphine resin (7.18 g, 15.43 mmol, 2.15 mmol/g loading) in tetrahydrofuran (100 mL) was 321 WO 2009/016498 PCT/IB2008/002046 cooled in an ice bath and di-tert-butylazodicarbxylate (2.84 g, 12.33 mmol) was added. The mixture was stirred for 10 minutes in the ice bath, allowed to warm to room temperature, and stirred an additional 2 hours. The reaction mixture was filtered and the resin was washed with tetrahydrofuran and methanol. The filtrate was concentrated and the residue was purified by reverse phase 5 preparative HPLC to afford the title compound as a white solid (1.58 g, 54%). MS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.06 - 1.21 (m, 2 H), 1.25 - 1.39 (m, 2 H), 1.58 - 1.70 (m, 2 H), 1.84 - 1.95 (m, 2 H), 1.95 - 2.08 (m, 1 H), 2.19 - 2.31 (m, 1 H), 2.67 (s, 3 H), 3.57 (s, 3 H), 3.73 (s, 3 H), 4.51 (d, J=6.18 Hz, 2 H), 4.67 (d, J=6.98 Hz, 2 H), 6.77 - 6.86 (m, 1 H), 6.88 - 6.97 (m, 2 H), 7.24 (t, J=8.19 Hz, 1 H), 8.07 (s, 1 H), 8.42 (s, 1 H), 9.26 (t, J=6.44 Hz, 1 H) 10 Example 268 (trans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2-yl)methyl) cyclohexanecarboxylic acid N H
-
N -H N OH N NO 0 A mixture of (trans)-methyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 15 tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 267) (2.729 g, 5.697 mmol), aqueous 2.5 N sodium hydroxide solution (28.515 mmol, 5 equiv.), water (114 mL), and tetrahydrofuran (114 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the aqueous residue was acidified. The precipitate was filtered, washed with water, and dried under high vacuum to afford the title compound as a solid (2.598 g, 98%). LC/MS (5%-95% 20 CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.217 min., m/z 465 (M+H). 1 H NMR (400 MHz, acetone-d) 6 ppm 1.15 - 1.32 (m, 2 H), 1.33 - 1.50 (m, 2 H), 1.72 - 1.83 (m, 2 H), 1.99 - 2.02 (m, J=3.22 Hz, 2 H), 2,07 - 2.18 (m, 1 H), 2.20 - 2.33 (m, 1 H), 2.64 (s, 3 H), 3.77 (s, 3 H), 4.64 (d, J=6.44 Hz, 2 H), 4.68 (d, J=6.98 Hz, 2 H), 6.82 (dd, J=8.32, 1.61 Hz, 1 H), 6.93 - 7.02 (m, 2 H), 7.24 (t, J=7.92 Hz, 1 H), 8.06 (d, J=1.07 Hz, 1 H), 8.61 (s, 1 H), 8.88 (s, 1 H). 25 Example 269 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(piperidine-1 -carbonyl)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide HN O O -0 N 0 - HN N I N To a vial containing piperidine, (13.79 mg, 0.162 mmol) added a solution of (trans)-4-((5-(2-((3 30 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid 322 WO 2009/016498 PCT/IB2008/002046 (prepared as described in Example 268) (51.0 mg, 0.108 mmol) and 1-hydroxybenzotriazole (2.9 mg, 0.022 mmol) in N,N-dimethylformamide (2 mL), followed by carbodiimide resin (125 mg, 0.162 mmol, 1.30 mmol/g loading), dichloromethane (2 mL), and N-methylmorpholine (54.54 mg, 0.54 mmol). The mixture was agitated on an orbital shaker overnight at room temperature. The mixture was filtered 5 and the resin was washed with N,N-dimethylformamide and dichloromethane. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min.) to afford the title compound (34.5 mg, 60%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95%
CH
3 CN, 1.5 min.): 3.705 min., m/z 532 (M+H). Example 270 10 4-(2-(((trans)-4-((2-Methoxyethyl)carbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-N-(3 methoxybenzyl)-6-methylpicolinamide _\ 0 N N N IN 0,11 -O N N N H The title compound (34.1 mg, 61%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(piperidine-1 -carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide 15 (Example 269) by reaction with 2-methoxyethanamine. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95%
CH
3 CN, 1.5 min.): 3.183 min., m/z 522 (M+H). Example 271 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(morpholine-4-carbonyl)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide - N O N N 20- N-N 0 20 The title compound (32.9 mg, 57%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(piperidine-1 -carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 269) by reaction with morpholine. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.259 min., m/z 534 (M+H). 25 Example 272 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(dimethylcarbamoyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 323 WO 2009/016498 PCT/IB2008/002046 HN O O O0 N N N HN NN - N - N'N/ The title compound (37.0 mg, 70%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(piperidine- 1 -carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 269) by reaction with dimethylamine. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 5 1.5 min.): 3.295 min., m/z 492 (M+H). Example 273 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(isopropylcarbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide - HN -0 N O NO N N N N x ' N - NN H 10 The title compound (16.6 mg, 30%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(piperidine- 1 -carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 269) by reaction with propan-2-amine. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95%
CH
3 CN, 1.5 min.): 3.422 min., m/z 506 (M+H). Example 274 15 4-(2-(((trans)-4-((2-Amino-2-oxoethyl)carbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-N-(3 methoxybenzyl)-6-methylpicolinamide HN O O -O N N N NH 2 N- NN H 0 The title compound (29.9 mg, 53%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(piperidine-1 -carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide 20 (Example 269) by reaction with 2-aminoacetamide. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95%
CH
3 CN, 1.5 min.): 2.861 min., m/z 521 (M+H). Example 275 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylcarbamoyl)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide 324 WO 2009/016498 PCT/IB2008/002046 SH N O O -0 N- NN N ~ IN - N H N 0-(7-Azabenzotriazole-1 -yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (49.0 mg, 0.130 mmol), methylamine (0.054 mL of a 2M solution in tetrahydrofuran, 0.108 mmol), and diisopropylethylamine (0.038 mL, 0.216 mmol) was added to a solution of (trans)-4-((5-(2-((3 5 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid (prepared as described in Example 268) (50.0 mg, 0,108 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min.) to afford the title compound as a solid (47.4 mg, 92%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 10 1.5 min.): 2.996 min., m/z 478 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.95 - 1.18 (m, 2 H), 1.21 - 1.43 (m, 2 H), 1.53 - 1.80 (m, 4 H), 1.87 - 2.13 (m, 1 H), 2.51 (d, J=4.39 Hz, 3 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 4.49 (d, J=6.59 Hz, 2 H), 4.65 (d, J=7.32 Hz, 2 H), 6.74 - 6.83 (m, 1 H), 6.90 (m, 2 H), 7.15 7.29 (m, 1 H), 7.48 - 7.64 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.11 - 9.29 (m, 1 H). Example 276 15 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(ethylcarbamoyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide HN O 0 N N - NN H The title compound (45.2 mg, 85%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(methylcarbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 20 275) by reaction with ethylamine. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.163 min., m/z 492 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.95 (t, J=7.32 Hz, 3 H), 1.00 1.15 (m, 2 H), 1.22 - 1.41 (m, 2 H), 1.52 - 1.82 (m, 4 H), 1.87 - 2.13 (m, 1 H), 2.65 (s, 3 H), 2.89 - 3.09 (m, 2 H), 3.71 (s, 3 H), 4.49 (d, J=6.59 Hz, 2 H), 4.65 (d, J=6.59 Hz, 2 H), 6.74 - 6.85 (m, 1 H), 6.90 (m, 2 H), 7.13 - 7.29 (m, 1 H), 7.51 - 7.68 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.08 - 9.26 (m, 1 H). 25 Example 277 4-(2-(((trans)-4-((2-Hydroxyethyl)carbamoyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-N-(3 methoxybenzyl)-6-methylpicolinamide 325 WO 2009/016498 PCT/IB2008/002046 0 - HN -O N:N N N OH - N'N H The title compound (45.2 mg, 85%) was prepared in a similar manner to N-(3-methoxybenzyl) 6-methyl-4-(2-(((trans)-4-(methylcarbamoyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 275) by reaction with 2-aminoethanol. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 5 2.835 min. 508 (M+H). 1 H NMR (400 MHz, DMSO-d) 5 ppm 0.96 - 1.19 (m, 2 H), 1.21 - 1.44 (m, 2 H), 1.54 - 1.80 (m, 4 H), 1.88 - 2.16 (m, 3 H), 2.65 (s, 3 H), 2.96 - 3.14 (m, 2 H), 3.71 (s, 3 H), 4.49 (d, J=5.86 Hz, 2 H), 4.65 (d, J=6.59 Hz, 2 H), 6.73 - 6.85 (m, 1 H), 6.90 (m, 2 H), 7.10 - 7.33 (m, 1 H), 7.50 - 7.68 (m, 1 H), 8.06 (s, 1 H), 8.41 (s, 1 H). Example 278 10 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol--yl)-6 methylpicolinamide N O H - N N / - NH 0 Formamide (120 mg) was added to a solution of (trans)-methyl 4-((5-(2-((3-methoxybenzyl) carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as 15 described in Example 267) (100 mg, 0.2 mmol) in anhydrous tetrahydrofuran (1 mL) and the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and then diluted with methanol (2 mL). The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title 20 compound as a white solid (77.5 mg). MS (ES+) m/z 464 (M+H). Example 279 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide N
-
H
-
N N 25 Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 500 mg) was added to N-(3 methoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 326 WO 2009/016498 PCT/IB2008/002046 (Example 278) (77.5 mg, 0.16 mmol) in a mixture of carbon tetrachloride (0.5 mL) and dichloroethane (4.5 mL) and the mixture was heated at 80 *C for 2 hours. The reaction mixture was filtered and the resin was washed with dichloroethane. The filtrate was concentrated and the residue was recrystallized from methanol to afford the title compound as a white solid (33.6 mg). MS (ES+) m/z 5 446 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.29 (t, J=6.6 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.25 (t, J=8.0 Hz, 1 H), 6.90 - 6.94 (m, 2 H), 6.83 (dd, J=8,1, 2.3 Hz, 1 H), 4.69 (d, J=6.8 Hz, 2 H), 4.51 (d, J=6.5 Hz, 2 H), 3.74 (s, 3 H), 2.68 (s, 3 H), 2.59 - 2.67 (m, 1 H), 1.98 - 2.13 (m, 3 H), 1.65 (d, J=13.1 Hz, 2 H), 1.45 - 1.56 (m, 2 H), 1.07 - 1.19 (m, 2 H). Example 280 10 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxyacetyl)cyclohexyl)methyl)-2H-tetrazo-5-y)-6 methylpicolinamide N OH
-
N/ H I NN N 0 H N-N OH 0 Oxalyl chloride (10 mL) was added to a solution of (trans)-4-((5-(2-((3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid 15 (prepared as described in Example 268) (1.4 g, 3.0 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperate for 3 hours. The reaction mixture was concentrated. The residue was taken up in dioxane (15 mL) and treated with tris(trimethylsiloxy)ethylene (1.94 g, 6.63 mmol). The mixture was heated to 90 *C for 3 hours and then stirred at room temperate for 18 hours. The mixture was treated with several drops of 4 N hydrochloric acid until gas stopped evolving. The reaction 20 mixture was purified by reverse phase preparative HPLC. The crude product was taken up in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a white solid (24 mg, 2%). LCMS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.06 - 1.41 (m, 4 H), 1.60 - 1.71 (m, J=10.98 Hz, 2 H), 1.85 - 1.96 (m, J=10.98 Hz, 2 H), 1.96 2.07 (m, 1 H), 2.20 - 2.31 (m, J=12.08, 12.08 Hz, 1 H), 2.67 (s, 3 H), 3.28 - 3.34 (m, 1 H), 3.57 (s, 2 25 H), 3.73 (s, 3 H), 4.51 (d, J=5.86 Hz, 2 H), 4.67 (d, J=6.59 Hz, 2 H), 6.82 (d, J=8.05 Hz, 1 H), 6.88 6.98 (m, 2 H), 7.24 (t, J=8.05 Hz, 1 H), 8.07 (s, 1 H), 8.43 (s, 1 H), 9.21 (t, J=6.22 Hz, 1 H). Example 281 (trans)-Methyl 4-((5-(2-((3-(Difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate 327 WO 2009/016498 PCT/IB2008/002046 0 F N H
-
N' F NN 0 A mixture of (3-(difluoromethoxy)phenyl)methanamine (380 mg, 2.2 mmol) and 4-(2-(((trans) 4-(methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (prepared as described in step 2 of the synthesis of (trans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6 5 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 260) (205 mg, 0.54 mmol) in N,N-dimethylacetamide (0.5 mL) was allowed to stir at room temperature for 3 days. The reaction mixture was purified by reverse phase preparative HPLC. The product containing fractions were passed through a carbonate resin column and concentrated. The residue was slurried with ethyl ether, decanted, and the solid was dried to afford the title compound (135 mg). MS (ES+) m/z 515 10 (M+H). Example 282 (trans)-4-((5-(2-((3-(Difluoromethoxy)benzyl)carbamoyl)-6-methypyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid F N H
-
N F N OH NN 0 15 Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (prepared as described in Example 281) (40 mg, 0.077 mmol) in a mixture of tetrahydrofuran/water (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase 20 preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (29 mg). MS (ES+) m/z 502 (M+H). Example 283 N-(3-(Difluoromethoxy)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5 yi)-6-methylpicolinamide 328 WO 2009/016498 PCT/IB2008/002046 0 N'" NN F H OH F N -O ON Lithium aluminum hydride (50 mg) was added to a solution of (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (prepared as described in Example 281) (53 mg, 0.1 mmol) in 5 anhydrous tetrahydrofuran (1 mL) cooled in an ice bath, The mixture was stirred at room temperature for 1 hour. Water (1 mL) was slowly added followed by acetonitrile (1 mL). The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC. Fractions containing the product were passed through a carbonate resin column. The crude product was slurried and decanted from ethyl ether several times, and dried in a vacuum desiccator to 10 afford the title compound as a white solid (28 mg). MS (ES+) m/z 487 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.39 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.10 (s, 1 H), 7.36 - 7.41 (m, 1 H), 7.21 - 7.24 (m, 1 H), 7.16 (s, 1 H), 7.03 - 7.09 (m, 2 H), 4.67 (d, J=7.0 Hz, 2 H), 4.55 (d, J=6.3 Hz, 2 H), 4.37 (t, J=5.2 Hz, 1 H), 3.19 (t, J=5.8 Hz, 2 H), 2.69 (s, 3 H), 1.91 - 2.03 (m, 1 H), 1.74 (d, J=1 1.4 Hz, 2 H), 1.62 (d, J=10.9 Hz, 2 H), 1.25 - 1.36 (m, 1 H), 1.02 - 1.15 (m, 2 H), 0.81 - 0.94 (m, 2 H). 15 Example 284 (trans)-Methyl 4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate F 0 H
-
N HN N /N g Tr. 0 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 20 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with 4-fluoro-3-methylbenzylamine to afford 172 mg as a solid. MS (ES+) m/z 481 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.30 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (d, J=0.9 Hz, 1 H), 7.26 (d, J=7.9 Hz, 1 H), 7.17 - 7.22 (m, 1 H), 7.05 - 7.11 (m, 1 H), 4.68 (d, J=6.8 Hz, 2 H), 4.48 (d, J=6.5 Hz, 2 H), 3.58 (s, 3 H), 2.68 (s, 3 H), 2.22 25 2.31 (m, 1 H), 2.21 (d, J=1.5 Hz, 3 H), 1.95 - 2.07 (m, 1 H), 1.91 (d, J=1 1.1 Hz, 2 H), 1.66 (d, J=1 3.0 Hz, 2 H), 1.26 - 1.39 (m, 2 H), 1.07 - 1.21 (m, 2 H). Example 285 (trans)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2 yl)methyl)cyclohexanecarboxylic acid 329 WO 2009/016498 PCT/IB2008/002046 F 0 N N ' OH NN 0 Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((4-fluoro-3 methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 284) (81 mg, 0.168 mmol) in a mixture of tetrahydrofuran/water 5 (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (71 mg). MS (ES+) m/z 467 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 12.12 (br. s., 1 H), 9.30 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.26 (d, J=7.7 Hz, 1 H), 7.17 - 7.22 (m, 1 H), 7.08 10 (t, J=9.6 Hz, 1 H), 4.68 (d, J=7.0 Hz, 2 H), 4.48 (d, J=6.3 Hz, 2 H), 2.68 (s, 3 H), 2.21 (d, J=11.4 Hz, 3 H), 2.08 - 2.17 (m, 1 H), 1.94 - 2.05 (m, 1 H), 1.90 (d, J=10.8 Hz, 2 H), 1.65 (d, J=12.5 Hz, 2 H), 1.22 1.36 (m, 2 H), 1.06 - 1.18 (m, 2 H). Example 286 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazo-5-yl)-6 15 methylpicolinamide F O H N H NH N\ ' ~ NH 2 0 Formamide (60 mg) was added to a solution of (trans)-methyl 4-((5-(2-((4-fluoro-3 methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 284) (50 mg, 0.1 mmol) in anhydrous tetrahydrofuran (0.6 mL) and 20 the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (60 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with excess methanol, and then concentrated. Methanol (2 mL) was added to the residue. The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (25.4 mg). MS (ES+) 25 m/z 466 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.30 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.26 (d, J=7.7 Hz, 1 H), 7.16 - 7.22 (m, 2 H), 7.08 (t, J=9.1 Hz, 1 H), 6.67 (br. s., 1 H), 4.68 (d, J=6.8 Hz, 2 H), 4.48 (d, J=6.3 Hz, 2 H), 2.68 (s, 3 H), 2.22 (d, J=1.0 Hz, 3 H), 2.02 (t, J=12.0 Hz, 2 H), 1.76 (d, J=10.9 Hz, 2 H), 1.65 (d, J=11.8 Hz, 2 H), 1.25 - 1.37 (m, 2 H), 1.03 - 1.15 (m, 2 H). 330 WO 2009/016498 PCT/IB2008/002046 Example 287 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F O - N N /' H N N " "O fCN 5 Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g) was added to N-(4-fluoro-3 methylbenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 286) (20 mg, 0.043 mmol) in a mixture of carbon tetrachloride (0.16 mL) and dichloroethane (1.5 mL) and the mixture was heated at 80 *C for 2 hours. The reaction mixture was filtered and the resin was washed with dichloroethane. The filtrate was concentrated to afford the title compound as a 10 white solid (9.7 mg). MS (ES+) m/z 448 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.30 (t, J=6.3 Hz, 1 H), 8.43 (s, 1 H), 8.09 (d, J=0.9 Hz, 1 H), 7,26 (d, J=7.3 Hz, 1 H), 7.17 - 7.22 (m, 1 H), 7.08 (t, J=9.1 Hz, 1 H), 4.69 (d, J=7.0 Hz, 2 H), 4.48 (d, J=6.3 Hz, 2 H), 2.68 (s, 3 H), 2.59 - 2.67 (m, 1 H), 2.22 (d, J=1.4 Hz, 3 H), 1.98 - 2.11 (m, 3 H), 1.65 (d, J=13.3 Hz, 2 H), 1.44 - 1.58 (m, 2 H), 1.05 - 1.19 (m, 2 H). 15 Example 288 (trans)-Methyl 4-((5-(2-((3-Ethylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate 0 - N H N N N , I 100-. N N 0 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 20 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with 3-ethylbenzylamine to afford 155 mg. MS (ES+) m/z 477 (M+H). Example 289 (trans)-4-((5-(2-((3-Ethylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 25 yl)methyl)cyclohexanecarboxylic acid 331 WO 2009/016498 PCT/IB2008/002046 0 - N H OH
N
0 The title compound was prepared in a similar manner to (trans)-4-((5-(2-((3-(difluoromethoxy) benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylic acid (Example 282) by reaction with(trans)-methyl 4-((5-(2-((3-ethylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 5 tetrazol-2-yl)methyl)cyclohexanecarboxylate (Example 288) to afford 45 mg as a white solid. MS (ES+) m/z 463 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 12.11 (br. s., 1 H), 9.27 (t, J=6.5 Hz, 1 H), 8.44 (s, 1 H), 8.09 (s, 1 H), 7.08 - 7.26 (m, 4 H), 4.68 (d, J=6.8 Hz, 2 H), 4.52 (d, J=6.3 Hz, 2 H), 2.68 (s, 3 H), 2.59 (q, J=7.6 Hz, 2 H), 2.09 - 2.17 (m, 1 H), 1.95 - 2.05 (m, 1 H), 1.90 (d, J=11.1 Hz, 2 H), 1.65 (d, J=10.6 Hz, 2 H), 1.23 - 1.36 (m, 2 H), 1.06 - 1.19 (m, 5 H). 10 Example 290 N-(3-Ethylbenzyl)-4-(2-(((trans)-4-carbamoyIcyclohexyl)methyl)-2H-tetrazo1-5-yl)-6 methylpicolinamide N 0 H
-
NNN N / / I NH 2 0 Formamide (120 mg) was added to a solution of (trans)-methyl 4-((5-(2-((3 15 ethylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 288) (80 mg, 0.16 mmol) in anhydrous tetrahydrofuran (1 mL) and the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and was diluted with methanol (2 mL). The mixture was stirred for 15 minutes and then 20 the resulting precipitate was filtered, washed with a small amount of methanol and dried in a vacuum desiccator to afford the title compound as a white solid (41 mg). MS (ES+) m/z 462 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.17 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.03 - 7.25 (m, 5 H), 6.58 (br. s., 1 H), 4.65 (d, J=7.0 Hz, 2 H), 4.50 (d, J=6.2 Hz, 2 H), 2.65 (s, 3 H), 2.56 (q, J=7.4 Hz, 2 H), 1.90 - 2.05 (m, 2 H), 1.74 (d, J=1 1.3 Hz, 2 H), 1.63 (d, J=1 1.0 Hz, 2 H), 1.22 - 1.36 (m, 2 H), 1.01 25 1.18 (m, 5 H). Example 291 (trans)-Methyl 4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate 332 WO 2009/016498 PCT/IB2008/002046 0 N NC H - N' N 0 N 0 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with 3-(aminomethyl)benzonitrile to 5 afford 157 mg as a white solid. MS (ES+) m/z 474 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.47 (t, J=6.3 Hz, 1 H), 8.43 (s, 1 H), 8.10 (s, 1 H), 7.79 (s, 1 H), 7.74 (d, J=7.7 Hz, 1 H), 7.70 (d, J=7.9 Hz, 1 H), 7.56 (t, J=7.8 Hz, 1 H), 4.68 (d, J=6.8 Hz, 2 H), 4.58 (d, J=6.1 Hz, 2 H), 3.58 (s, 3 H), 2.69 (s, 3 H), 2.22 - 2.31 (m, 1 H), 1.96 - 2.06 (m, 1 H), 1.91 (d, J=1 1.1 Hz, 2 H), 1.65 (d, J=10.8 Hz, 2 H), 1.33 (q, J=12.6 Hz, 2 H), 1.07 - 1.21 (m, 2 H). 10 Example 292 (trans)-4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid - N NC H - N N ' OH 0 Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((3 15 cyanobenzyl)carba moyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 291) (81 mg, 0.17 mmol) in a mixture of tetrahydrofuran/water (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white 20 solid (45 mg). MS (ES+) m/z 460 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.46 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.10 (d, J=0.9 Hz, 1 H), 7.79 (s, 1 H), 7.67 - 7.76 (m, 2 H), 7.56 (t, J=7.7 Hz, 1 H), 4.66 (d, J=7.0 Hz, 2 H), 4.58 (d, J=6.5 Hz, 2 H), 2.69 (s, 3 H), 1.92 - 2.02 (m, 2 H), 1.87 (d, J=10.9 Hz, 2 H), 1.61 (d, J=10.8 Hz, 2 H), 1.18 - 1.31 (m, 2 H), 1.01 - 1.15 (m, 2 H). Example 293 25 (trans)-Methyl 4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate 333 WO 2009/016498 PCT/IB2008/002046 N H N O H - N .NA N I NN 0 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with (3-ethoxyphenyl)methanamine 5 (prepared as described in step 2 of the synthesis of N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide, Example 180) to afford 182 mg as a white solid. MS (ES+) m/z 493 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.28 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (d, J=0.9 Hz, 1 H), 7.23 (t, J=8.0 Hz, 1 H), 6.89 - 6.92 (m, 2 H), 6.80 (dd, J=8.0, 1.9 Hz, 1 H), 4.68 (d, J=7.0 Hz, 2 H), 4.50 (d, J=6.5 Hz, 2 H), 4.00 (q, J=6.9 Hz, 2 H), 3.58 (s, 3 H), 10 2.68 (s, 3 H), 2.21 - 2.31 (m, 1 H), 1.97 - 2.07 (m, 1 H), 1.91 (d, J=10.6 Hz, 2 H), 1.66 (d, J=10.6 Hz, 2 H), 1.27 - 1.39 (m, 5 H), 1.09 - 1.21 (m, 2 H). Example 294 (trans)-4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylic acid 0 -NO 0 H N -OH 15 O Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((3 ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 293) (78 mg, 0.15 mmol) in a mixture of tetrahydrofuran/water (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was 20 acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (7 mg). MS (ES+) m/z 479 (M+H). Example 295 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)- 6 25 methylpicolinamide 334 WO 2009/016498 PCT/IB2008/002046 - N HN NH2 NN / INH 0 Formamide (120 mg) was added to a solution of (trans)-methyl 4-((5-(2-((3 ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 293) (85 mg, 0.17 mmol) in anhydrous tetrahydrofuran (1 mL) and 5 the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with excess methanol, and was concentrated. Methanol (2 mL) was added to the residue. The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (33 mg). MS (ES+) m/z 10 478 (M+H). Example 296 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 0 N O O H N /-0 N N - " 'D CN 15 Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 200 mg) was added to N-(3 ethoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazo-5-yl)-6-methylpicolinamide (Example 295) (30 mg, 0.062 mmol) in a mixture of carbon tetrachloride (0.25 mL) and dichloroethane (2.25 mL) and the mixture was heated at 80 *C for 2 hours. The reaction mixture was filtered and the resin was washed with dichloroethane. The filtrate was concentrated and the residue was purified by 20 reverse phase preparative HPLC. Fractions containing product were passed through a carbonate resin column and were concentrated. The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (18.3 mg). MS (ES+) m/z 460 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.18 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.20 (t, J=8.1 Hz, 1 H), 6.85 - 6.90 (m, 2 H), 6.78 (d, J=8.8 Hz, 1 H), 4.65 (d, J=7.3 Hz, 2 25 H), 4.48 (d, J=5.9 Hz, 2 H), 3.97 (q, J=7.3 Hz, 2 H), 2.65 (s, 3 H), 2.56 - 2.64 (m, 1 H), 1.95 - 2.11 (m, 3 H), 1.63 (d, J=11.0 Hz, 2 H), 1.49 (q, J=12.7 Hz, 2 H), 1.28 (t, J=7.0 Hz, 3 H), 1.05 - 1.17 (m, 2 H). Example 297 (trans)-Methyl 4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol 2-yl)methyl)cyclohexanecarboxylate 335 WO 2009/016498 PCT/IB2008/002046 F 0 - N O N N 0 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with 4-fluoro-3-methoxybenzylamine 5 (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) to afford 121 mg as a white solid. MS (ES+) m/z 497 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.31 (t, J=6.3 Hz, 1 H), 8.43 (s, 1 H), 8.09 (d, J=0.9 Hz, 1 H), 7.19 (dd, J=8.5, 1.9 Hz, 1 H), 7.15 (dd, J=11.6, 8.4 Hz, 1 H), 6.87 - 6.93 (m, 1 H), 4.68 (d, J=7.0 Hz, 2 H), 4.50 (d, J=6.5 Hz, 2 H), 3.82 (s, 3 H), 3.58 (s, 3 H), 2.68 10 (s, 3 H), 2.21 - 2.31 (m, 1 H), 1.98 (br. s., 1 H), 1.92 (d, J=13.3 Hz, 2 H), 1.65 (d, J=10.6 Hz, 2 H), 1.26 - 1.39 (m, 2 H), 1.09 - 1.20 (m, 2 H). Example 298 (trans)-4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2 yl)methyl)cyclohexanecarboxylic acid F N O H N H OH 15 0 Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 297) (63 mg, 0.13 mmol) in a mixture of tetrahydrofuran/water (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight, The reaction mixture was 20 acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (30 mg). MS (ES+) m/z 483 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.30 (t, J=6.3 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.19 (dd, J=9.0, 2.1 Hz, 1 H), 7.15 (dd, J=11.6, 8.4 Hz, 1 H), 6.88 - 6.93 (m, 1 H), 4.67 (d, J=6.8 Hz, 2 H), 4.50 (d, J=6.3 Hz, 2 H), 3.82 (s, 3 H), 2.68 (s, 3 H), 1.93 - 2.12 (m, 2 25 H), 1.89 (d, J=10.9 Hz, 2 H), 1.63 (d, J=10.9 Hz, 2 H), 1.28 (q, J=12.5 Hz, 2 H), 1.05 - 1.18 (m, 2 H) Example 299 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 336 WO 2009/016498 PCT/IB2008/002046 F N S H N H NH 0 Formamide (720 mg) was added to a solution of (trans)-methyl 4-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 297) (476 mg (0.95 mmol) in anhydrous tetrahydrofuran (6 mL) 5 and the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (720 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with methanol (6 mL), and then concentrated. Methanol (3 mL) was added to the residue. The resulting precipitate was filtered, washed with methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (262 mg). MS (ES+) m/z 482 (M+H). 10 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.31 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.12 - 7.23 (m, 3 H), 6.91 (dd, J=6.1, 3.9 Hz, 1 H), 6.67 (br. s., 1 H), 4.68 (d, J=7.0 Hz, 2 H), 4.51 (d, J=6.1 Hz, 2 H), 3.83 (s, 3 H), 2.68 (s, 3 H), 1.94 - 2.07 (m, 2 H), 1.76 (d, J=12.1 Hz, 2 H), 1.65 (d, J=12.1 Hz, 2 H), 1.24 - 1.38 (m, 2 H), 1.03 - 1.16 (m, 2 H). Example 300 15 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F 0 O N NN Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 1 g) was added to N-(4-fluoro 3-methoxybenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 20 (Example 299) (223 mg, 0.46 mmol) in a mixture of carbon tetrachloride (1.5 mL) and dichloroethane (13.5 mL) and the mixture was heated at 80 *C for 2 hours. The reaction mixture was filtered and the resin was washed with dichloroethane. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC. The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (139 mg). 25 MS (ES+) m/z 464 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.31 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (d, J=0.9 Hz, 1 H), 7.19 (dd, J=8.5, 1.7 Hz, 1 H), 7.15 (dd, J=11.6, 8.2 Hz, 1 H), 6.87 - 6.93 (m, 1 H), 4.69 (d, J=6.8 Hz, 2 H), 4.50 (d, J=6.3 Hz, 2 H), 3.83 (s, 3 H), 2.68 (s, 3 H), 2.58 - 2.67 (m, 1 H), 1.98 - 2.12 (m, 3 H), 1.65 (dd, J=13.2, 2.6 Hz, 2 H), 1.44 - 1.57 (m, 2 H), 1.07 - 1.19 (m, 2 H). 337 WO 2009/016498 PCT/IB2008/002046 Example 301 (trans)-Methyl 4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2 yl)methyl)cyclohexanecarboxylate F N CI H
-
N N OsI N 0 5 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with 3-chloro-4-fluorobenzylamine to afford 123 mg as a white solid. MS (ES+) m/z 501 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.43 (t, J=6.4 Hz, 1 H), 8.42 (s, 1 H), 8.10 (d, J=0.7 Hz, 1 H), 7.56 (d, J=7.9 Hz, 1 H), 7.35 - 7.40 (m, 2 H), 10 4.68 (d, J=7.0 Hz, 2 H), 4.51 (d, J=6.3 Hz, 2 H), 3.58 (s, 3 H), 2.69 (s, 3 H), 2.21 - 2.31 (m, 1 H), 1.96 2.07 (m, 1 H), 1.91 (d, J=11.1 Hz, 2 H), 1.65 (d, J=10.8 Hz, 2 H), 1.27 - 1.38 (m, 2 H), 1.09 - 1.21 (m, 2 H). Example 302 (trans)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazo-2 15 yl)methyl)cyclohexanecarboxylic acid F N SN N N OH N':N 0 Sodium hydroxide (1 pellet) was added to a solution of (trans)-methyl 4-((5-(2-((3-chloro-4 fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 301) (65 mg, 0.13 mmol) in a mixture of tetrahydrofuran/water (0.6 20 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (41 mg). MS (ES+) m/z 487 (M+H). 'H NMR (400 MHz, DMSO-dr) 6 ppm 9.49 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 8.10 (s, 1 H), 7.78 (d, J=7.0 Hz, 1 H), 7.71 - 7.75 (m, 1 H), 7.45 - 7.52 (m, 1 H), 4.68 25 (d, J=6.8 Hz, 2 H), 4.58 (d, J=6.3 Hz, 2 H), 3.58 (s, 3 H), 2.69 (s, 3 H), 2.20 - 2.30 (m, 1 H), 1.96 - 2.04 (m, 1 H), 1.91 (d, J=13.0 Hz, 2 H), 1.66 (d, J=12.8 Hz, 2 H), 1.26 - 1.39 (m, 2 H), 1.08 - 1.20 (m, 2 H). Example 303 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 338 WO 2009/016498 PCT/IB2008/002046 F 0 Cl H N N I NH 2 0 Formamide (720 mg) was added to a solution of (trans)-methyl 4-((5-(2-((3-chloro-4 fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 301) (268 mg, 0.53 mmol) in anhydrous tetrahydrofuran (6 mL) 5 and the mixture was heated to reflux. A 25% sodium methoxide solution in methanol (720 mg) was added and the reaction was stirred at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with methanol (6 mL), and then concentrated. Methanol (3 mL) was added to the residue. The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (135 mg). MS 10 (ES+) m/z 486 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.43 (t, J=6.4 Hz, 1 H), 8.42 (s, 1 H), 8.10 (s, 1 H), 7.56 (d, J=7.0 Hz, 1 H), 7.37 (d, J=7.9 Hz, 2 H), 7.17 (br. s., 1 H), 6.67 (br. s., 1 H), 4.68 (d, J=6.8 Hz, 2 H), 4.51 (d, J=6.5 Hz, 2 H), 2.69 (s, 3 H), 1.92 - 2.07 (m, 2 H), 1.76 (d, J=11.1 Hz, 2 H), 1.64 (d, J=10.8 Hz, 2 H), 1.25 - 1.38 (m, 2 H), 1.03 - 1.15 (m, 2 H). Example 304 15 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-cyanocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F N Cl H
-
N N N/C NO Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 1 g) was added to N-(3 chloro-4-fluorobenzyl)-4-(2-(((trans)-4-carbamoylcyclohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinamide (Example 303) (100 mg, 0.2 mmol) in a mixture of carbon tetrachloride (1.5 mL) and dichloroethane (13.5 mL) and the mixture was heated at 80 0C for 2 hours. The reaction mixture was filtered and the resin was washed with methanol. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC. Fractions containing product were passed through a carbonate resin column and then concentrated. The product was slurried and decanted several 25 times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (33.9 mg). MS (ES+) m/z 468 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.43 (t, J=6.4 Hz, 1 H), 8.42 (s, 1 H), 8.09 (d, J=1.0 Hz, 1 H), 7.53 - 7.59 (m, 1 H), 7.35 - 7.41 (m, 2 H), 4.69 (d, J=6.8 Hz, 2 H), 4.51 (d, J=6.3 Hz, 2 H), 2.69 (s, 3 H), 2.58 - 2.67 (m, 1 H), 1.98 - 2.13 (m, 3 H), 1.60 1.69 (m, 2 H), 1.45 - 1.57 (m, 2 H), 1.07 - 1.19 (m, 2 H). 339 WO 2009/016498 PCT/IB2008/002046 Example 305 (trans)-Methyl 4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6-methylpyridin-4-y)-2H tetrazol-2-yl)methyl)cyclohexanecarboxylate F ;0 F - HN N F F N N ' F N I 0 5 The title compound was prepared in a similar manner to (trans)-methyl 4-((5-(2-((3 (difluoromethoxy)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (Example 281) by reaction with (4-fluoro-3 (trifluoromethyl)phenyl)methanamine to afford 143 mg as a white solid. MS (ES+) m/z 535 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.49 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 8.10 (s, 1 H), 7.76 - 7.79 (m, 1 10 H), 7.71 - 7.76 (m, 1 H), 7.48 (dd, J=10.5, 8.5 Hz, 1 H), 4.68 (d, J=6.8 Hz, 2 H), 4.58 (d, J=6.3 Hz, 2 H), 3.58 (s, 3 H), 2.69 (s, 3 H), 2.20 - 2.31 (m, 1 H), 1.91 (d, J=1 1.9 Hz, 2 H), 1.65 (d, J=14.7 Hz, 2 H), 1.26 - 1.39 (m, 2 H), 1.08 - 1.21 (m, 2 H) Example 306 (trans)-4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 15 tetrazol-2-yl)methyl)cyclohexanecarboxylic acid F 0 F HN N-' F F N OH F --- INON /I 0 Sodium hydroxide (1 pellet) was added to a solution of trans)-methyl 4-((5-(2-((4-fluoro-3 (trifluoromethyl)benzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexanecarboxylate (prepared as described in Example 305) (68 mg, 0.13 mmol) in a 20 mixture of tetrahydrofuran/water (0.6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC. The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (46 mg). MS (ES+) m/z 521 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.49 (t, J=6.3 Hz, 1 H), 8.42 (s, 1 H), 8.10 (s, 1 H), 7.76 - 7.80 (m, 1 H), 7.71 - 7.75 25 (m, 1 H), 7.48 (dd, J=10.7, 8.8 Hz, 1 H), 4.67 (d, J=6.8 Hz, 2 H), 4.58 (d, J=6.3 Hz, 2 H), 2.69 (s, 3 H), 2.06 - 2.15 (m, 1 H), 1.94 - 2.03 (m, 1 H), 1.86 - 1.93 (m, 2 H), 1.64 (d, J=12.5 Hz, 2 H), 1.22 - 1.35 (m, 2 H), 1.05 - 1.18 (m, 2 H). Example 307 N-((2,3-Dihydrobenzofuran-5-yl)methyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H 30 tetrazol-5-yi)-6-methylpicolinamide 340 WO 2009/016498 PCT/IB2008/002046 0 N~ N " NH N OH O N Step 1: Preparation of methyl 4-(2-(((trans)-4-(hydroxymethyl)cvclohexvl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate 0 0 N/ \ NaN N x, I OH - N'N 1.,,O 5 Methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (2.19 g, 10.0 mmol), polymer supported triphenylphosphine (9.3 g, 20.0 mmol), and trans-cyclohexane-1,4-dimethanol (2.88 g, 20.0 mmol) were suspended in tetrahydrofuran (200 mL). The mixture was cooled to 0 *C. Di-tert-butyl azodicarboxylate (4.6 g, 20.0 10 mmol) was added. The mixture was allowed to warm to room temperature and stir for 18 hours. The reaction mixture was filtered and the resin washed with tetrahydrofuran (100 mL). The filtrate was concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2; 100/4) to afford the title compound as 15 an oil (2.3 g, 67%). MS (ES+) m/z 346 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 8.40 (d, J=0.8 Hz, 1 H), 8.12 (d, J=1.1 Hz, 1 H), 4.67 (d, J=7.0 Hz, 2 H), 4.35 (t, J=5.3 Hz, 1 H), 3.93 (s, 3 H), 3.19 (t, J=5.8 Hz, 2 H), 2.66 (s, 3 H), 2.04 - 1.90 (m, 1 H), 1.74 (d, J=10.6 Hz, 2 H), 1.61 (d, J=10.6 Hz, 2 H), 1.37 - 1.23 (m, 1 H), 1.08 (dq, J=12.6, 2.7 Hz, 2 H), 0.87 (dq, J=12.8, 3.1 Hz, 2 H). Step 2: Preparation of 4-(2-(((trans)-4-(hydroxymethvl)cyclohexyl)methyl)-2H-tetrazol-5-vl)-6 20 methylpicolinic acid 0 HO N \ N.aN N x-< I OH - - N Methyl 4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (2.3 g, 6.68 mmol) was dissolved in a mixture of tetrahydrofuran/water (40 mL, 1/1). Lithium hydroxide (479 mg, 20.0 mmol) was added and the mixture was stirred at room temperature for 3 hours. The 25 solvent was removed in vacuo and the residue was diluted with water (20 mL). The solution was made acidic with 1N hydrochloric acid solution (20 mL) and the resulting precipitate was filtered to afford the title compound as a white solid (1.03 g, 47%). MS (ES+) m/z 332 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 13.36 (br, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.09 (d, J=1.1 Hz, 1 H), 4.66 (d, J=7.1 341 WO 2009/016498 PCT/IB2008/002046 Hz, 2 H), 4.35 (br, 1 H), 3.19 (d, J=6.2 Hz, 2 H), 2.65 (s, 3 H), 2.03 - 1.90 (m, 1 H), 1.74 (d, J=10.5 Hz, 2 H), 1.61 (d, J=10.9, 2 H), 1.35 - 1.25 (m, 1 H), 1.08 (dg, J=12.6, 2.8 Hz, 2 H), 0.87 (dg, J=12.8, 3.2 Hz, 2 H). Step 3: Preparation of N-((2,3-dihydrobenzofuran-5-yl)methyl)-4-(2-(((trans)-4 5 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-vl)-6-methylpicolinamide 0 / N ~. -. NH
.
OH O N A mixture of 4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinic acid (33 mg, 0.10 mmol) and 1-hydroxybenzotriazole (18.9 mg, 0.14 mmol) in N,N dimethylformamide (0.5 mL) was shaken for 15 minutes. N-Methylmorpholine (44 pL, 0.40 mmol) was 10 added followed by (2,3-dihydrobenzofuran-5-yl)methanamine (17.9 mg, 0.12 mmol) in N,N dimethylformamide (0.5 mL). 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (26.8 mg, 0.14 mmol) was then added and the mixture was shaken for 18 hours. The reaction mixtures were purified by preparative reverse phase preparative HPLC to afford the title compound (33 mg). MS (ES+) m/z 463 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 10.48 (s, 0.5 H), 9.11 (t, J=6.2 Hz, 1 H), 15 8.37 (s, 1 H), 8.02 (s, 1 H), 7.18 (s, 1 H), 7.03 (d, J=7.7 Hz, 1 H), 6.64 (d, J=8.1 Hz, 1 H), 4.61 (d, J=7.0 Hz, 2 H), 4.44 (t, J=8.8 Hz, 2 H), 4.39 (d, J=6.6 Hz, 2 H), 4.32 (t, J=5.1 Hz, 1 H), 3.14 (t, J=5.5 Hz, 2 H), 3.09 (t, J=8.8 Hz, 2 H), 2.61 (s, 3 H), 1.99 - 1.84 (m, 1 H), 1.69 (d, J=12.8 Hz, 2 H), 1.56 (d, J=11.7 Hz, 2 H), 1.30 - 1.19 (m, 1 H), 1.03 (q, J=11.7 Hz, 2 H), 0.82 (q, J=12.2 Hz, 2 H). Example 308 20 N-(3-(Trifluoromethyl)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide NN
F
3 C NN NH N OH O N 3-Trifluoromethylbenzylamine was reacted according to procedures described in Example 307 to afford the title compound (37 mg). MS (ES+) m/z 489 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 25 9.43 (t, J=6.2 Hz, 1 H), 8.37 (s, 1 H), 8.04 (s, 1 H), 7.69 - 7.48 (m, 4 H), 4.61 (d, J=7.0 Hz, 2 H), 4.56 (d, J=6.2 Hz, 2 H), 4.31 (t, J=5.1 Hz, 1 H), 3.13 (t, J=5.7 Hz, 2 H), 2.63 (s, 3 H), 1.98 - 1.85 (m, 1 H), 1.68 (d, J=11.7 Hz, 2 H), 1.56 (d, J=11.3 Hz, 2 H), 1.31 - 1.19 (m, 1 H), 1.02 (q, J=12.8 Hz, 2 H), 0.82 (q, J=12.4 Hz, 2 H). 342 WO 2009/016498 PCT/IB2008/002046 Example 309 N-(3-(Trifluoromethoxy)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol 5-yi)-6-methylpicolinamide FC N' N -I NH N O H 0 N 5 3-Trifluoromethoxybenzylamine was reacted according to procedures described in Example 307 to afford the title compound (31 mg). MS (ES+) m/z 527 (M+H), 'H NMR (400 MHz, DMSO-d) 6 ppm 9.40 (t, J=6.4 Hz, 1 H), 8.38 (s, 1 H), 8.05 (s, 1 H), 7.43 (t, J=7.9 Hz, 1 H), 7.34 (d, J=7.7 Hz, 1 H), 7.29 (s, 1 H), 7.21 (d, J=8.1 Hz, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.53 (d, J=6.2 Hz, 2 H), 4.32 (t, J=5.3 Hz, 1 H), 3.14 (t, J=5.7 Hz, 2 H), 2.64 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.70 (d, J=12.4 Hz, 2 H), 10 1.57 (d, J=11.7 Hz, 2 H), 1.31 - 1.20 (m, 1 H), 1.03 (q, J=13.2 Hz, 2 H), 0.83 (q, J=12.8 Hz, 2 H). Example 310 N-(3-Chlorobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide NH N OH 0 N 15 3-Chlorobenzylamine was reacted according to procedures described in Example 307 to afford the title compound (16 mg). MS (ES+) m/z 455 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.37 (t, J=6.4 Hz, 1 H), 8.38 (s, 1 H), 8.05 (s, 1 H), 7.26 - 7.37 (m, 4 H), 4.62 (d, J=7.0 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 4.33 (t, J=5.3 Hz, 1 H), 3.14 (t, J=5.7 Hz, 2 H), 2.64 (s, 3 H), 1.97 - 1.87 (m, 1 H), 20 1.70 (d, J=10.6 Hz, 2 H), 1.57 (d, J=11.3 Hz, 2 H), 1.31 - 1.21 (m, 1 H), 1.03 (q, J=12.4 Hz, 2 H), 0.83 (q, J=12.4 Hz, 2 H). Example 311 N-(3-Methylbenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 343 WO 2009/016498 PCT/IB2008/002046 NH N OH 0 N 3-Methylbenzylamine was reacted according to procedures described in Example 307 to afford the title compound (33 mg). MS (ES+) m/z 435 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.4 Hz, 1 H), 8.39 (s, 1 H), 8.04 (s, 1 H), 7.17 (t, J=7.5 Hz, 1 H), 7.07 - 7.13 (m, 2 H), 7.02 5 (d, J=7.3 Hz, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.46 (d, J=6.2 Hz, 2 H), 4.32 (t, J=5.1 Hz, 1 H), 3.14 (t, J=5.9 Hz, 2 H), 2.63 (s, 3 H), 2.24 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.70 (d, J=11.0 Hz, 2 H), 1.57 (d, J=11.3 Hz, 2 H), 1.30 - 1.20 (m, 1 H), 1.04 (q, J=13.2 Hz, 2 H), 0.83 (q, J=12.2 Hz, 2 H). Example 312 N-(3-Ethylbenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 10 methylpicolinamide N' N NH - OH O N 3-Ethylbenzylamine was reacted according to procedures described in Example 307 to afford the title compound (32 mg). MS (ES+) m/z 449 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.38 (s, 1 H), 8.03 (s, 1 H), 7.21 - 7.02 (m, 4 H), 4.61 (d, J=7.0 Hz, 2 H), 4.46 (d, J=6.6 Hz, 2 H), 15 4.32 (t, J=5.3 Hz, 1 H), 3.14 (t, J=5.7 Hz, 2 H), 2.62 (s, 3 H), 2.53 (q, J=7.6 Hz, 2 H), 1.97 - 1.87 (m, 1 H), 1.69 (d, J=1 1.0 Hz, 2 H), 1.56 (d, J=10.2 Hz, 2 H), 1.30 - 1.20 (m, 1 H), 1.11 (t, J=7.7 Hz, 3 H), 1.03 (q, J=12.4 Hz, 2 H), 0.82 (q, J=12.1 Hz, 2 H), Example 313 N-(3-1sopropoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 20 methylpicolinamide 0 N0N NH N' OH 0 N 3-lsopropoxybenzylamine was reacted according to procedures described in Example 307 to afford the title compound (37 mg). MS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.38 (s, 1 H), 8.04 (s, 1 H), 7.16 (t, J=8.1 Hz, 1 H), 6.87 - 6.72 (m, 3 H), 4.61 25 (d, J=7.0 Hz, 2 H), 4.52 (qq, J=5.9 Hz, 1 H), 4.44 (d, J=6.2 Hz, 2 H), 4.31 (t, J=5.1 Hz, 1 H), 3.14 (t, 344 WO 2009/016498 PCT/IB2008/002046 J=5.7 Hz, 2 H), 2.63 (s, 3 H), 1.98 - 1.86 (m, 1 H), 1.69 (d, J=1 1.3 Hz, 2 H), 1.56 (d, J=1 1.0 Hz, 2 H), 1.30 - 1.19 (m, 1 H), 1.19 (d, J=5.9 Hz, 6 H), 1.03 (q, J=12.8 Hz, 2 H), 0.82 (q, J=12.4 Hz, 2 H). Example 314 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 5 methylpicolinamide N N _, O NH N OH 0 N (3-Ethoxyphenyl)methanamine (prepared as described in step 2 of the synthesis of N-(3 ethoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide, Example 180) was reacted according to procedures described in Example 307 to 10 afford the title compound (36 mg). MS (ES+) m/z 465 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.38 (s, 1 H), 8.04 (s, 1 H), 7.18 (t, J=8.1 Hz, 1 H), 6.88 - 6.83 (m, 2 H), 6.76 (d, J=8.4 Hz, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.46 (d, J=6.2 Hz, 2 H), 4.33 (t, J=5.3 Hz, 1 H), 3.95 (q, J=7.0 Hz, 2 H), 3.14 (t, J=5.7 Hz, 2 H), 2.63 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.69 (d, J=12.4 Hz, 2 H), 1.57 (d, J=12.4 Hz, 2 H), 1.26 (t, J=7.0 Hz, 3 H), 1.28 - 1.20 (m, 1 H), 1.04 (q, J=12.4 Hz, 2 H), 0.83 15 (q, J=11.3 Hz, 2 H). Example 315 N-(3,4-Difluorobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide F FNH FN N OH 0 N 20 3,4-Difluorobenzylamine was reacted according to procedures described in Example 307 to afford the title compound (33 mg). MS (ES+) m/z 457 (M+H). 'H NMR (400 MHz, DMSO-de) 6 ppm 9.36 (t, J=6.4 Hz, 1 H), 8.38 (s, 1 H), 8.05 (s, 1 H), 7.39 - 7.30 (m, J=8.5, 8.5, 8.5 Hz, 2 H), 7.13 - 7.18 (m, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4,47 (d, J=6.6 Hz, 2 H), 4.32 (t, J=5.3 Hz, 1 H), 3.14 (t, J=5.9 Hz, 2 H), 2.64 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.70 (d, J=11.0 Hz, 2 H), 1.57 (d, J=12.1 Hz, 2 H), 1.30 - 1.18 25 (m, 1 H), 1.03 (q, J=12.8 Hz, 2 H), 0.83 (q, J=11.3 Hz, 2 H). Example 316 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide 345 WO 2009/016498 PCT/IB2008/002046 F N' N NH - OH O N 4-Fluoro-3-methylbenzylamine was reacted according to procedures described in Example 307 to afford the title compound (35 mg). MS (ES+) m/z 453 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.25 (t, J=6.2 Hz, 1 H), 8.38 (s, 1 H), 8.04 (s, 1 H), 7,21 (d, J=7.3 Hz, 1 H), 7.17 - 7.13 (m, 1 H), 5 7.03 (t, J=9.2 Hz, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.43 (d, J=6.2 Hz, 2 H), 4.32 (t, J=5.1 Hz, 1 H), 3.14 (t, J=5.7 Hz, 2 H), 2.63 (s, 3 H), 2.17 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.70 (d, J=11.0 Hz, 2 H), 1.57 (d, J=13.2 Hz, 2 H), 1.30 - 1.20 (m, 1 H), 1.03 (q, J=10.6 Hz, 2 H), 0.83 (q, J=12.4 Hz, 2 H). Example 317 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexy)methyl)-2H 10 tetrazol-5-yl)-6-methylpicolinamide F
F
3 C N'N NH -N OH O N 4-Fluoro-3-trifluorobenzylamine was reacted according to procedures described in Example 307 to afford the title compound (30 mg). MS (ES+) m/z 507 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.43 (t, J=6.2 Hz, 1 H), 8.37 (s, 1 H), 8.05 (s, 1 H), 7.73 (d, J=6.2 Hz, 1 H), 7.71 - 7.66 (m, 1 H), 15 7.47 - 7.40 (m, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.53 (d, J=6.2 Hz, 2 H), 4.32 (t, J=5.3 Hz, 1 H), 3.14 (t, J=5.5 Hz, 2 H), 2.64 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.69 (d, J=10.6 Hz, 2 H), 1.57 (d, J=11.3 Hz, 2 H), 1.30 - 1.20 (m, 1 H), 1.03 (q, J=12.8 Hz, 2 H), 0.83 (q, J=12.4 Hz, 2 H). Example 318 N-(3-(Hydroxymethyl)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5 20 yl)-6-methylpicolinamide NH N' NOH O N (3-(Aminomethyl)phenyl)methanol was reacted according to procedures described in Example 307 to afford the title compound (34 mg). MS (ES+) m/z 451 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.39 (s, 1 H), 8.04 (s, 1 H), 7.12 - 7.29 (m, 4 H), 5.13 (t, J=5.7 Hz, 1 H), 25 4.62 (d, J=7.0 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 4.43 (d, J=5.5 Hz, 2 H), 4.33 (t, J=5.1 Hz, 1 H), 3.14 346 WO 2009/016498 PCT/IB2008/002046 (t, J=5.7 Hz, 2 H), 2.63 (s, 3 H), 1.97 - 1.87 (m, 1 H), 1.70 (d, J=1 1.0 Hz, 2 H), 1.57 (d, J=1 1.0 Hz, 2 H), 1.30 - 1.20 (m, 1 H), 1.03 (q, J=12.1 Hz, 2 H), 0.83 (q, J=12.1 Hz, 2 H). Example 319 N-(3-Hydroxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-y)-6 5 methylpicolinamide HONH N OH O N 3-Hydroxybenzylamine was reacted according to procedures described in Example 307 to afford the title compound (34 mg). MS (ES+) m/z 437 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.27 (s, 1 H), 9.18 (t, J=6.0 Hz, 1 H), 8.38 (s, 1 H), 8.04 (s, 1 H), 7.06 (t, J=7.9 Hz, 1 H), 6.73 - 6.67 10 (m, 2 H), 6.57 (d, J=8.8 Hz, 1 H), 4.62 (d, J=7.0 Hz, 2 H), 4.40 (d, J=6.2 Hz, 2 H), 4.32 (t, J=5.1 Hz, 1 H), 3.14 (t, J=5.5 Hz, 2 H), 2.63 (s, 3 H), 1.98 - 1.86 (m, 1 H), 1.69 (d, J=1 1.3 Hz, 2 H), 1.56 (d, J=1 1.0 Hz, 2 H), 1.31 - 1.20 (m, 1 H), 1.03 (q, J=12.8 Hz, 2 H), 0.82 (q, J=12.8 Hz, 2 H). Example 320 N-(3-Fluoro-5-methoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 15 yl)-6-methylpicolinamide F 0 NN NH N OH O N Step 1: Preparation of (3-fluoro-5-methoxyphenyl)methanamine F O - NH 2 To a suspension of lithium aluminum hydride ( 3.3 mL, 2.0 M in tetrahydrofuran) was added 20 dropwise a solution of 3-fluoro-5-methoxybenzonitrile (0.20 g, 1.34 mmol) in tetrahydrofuran (5.0 mL) at 0 *C. After 2 h, a saturated solution of sodium sulfate (2-3 mL) was added dropwise until hydrogen gas evolution ceased. The precipitate was filtered off and the filtrate was diluted with ethyl acetate ( 10 mL). The organic layer was separated, washed with water (2 x 5 mL), brine (5 mL), dried over sodium sulfate, and concentrated to afford the title compound (0.14 g, 69%). 'H NMR (400 MHz, DMSO-d 6 ) 6 25 ppm 6.68 - 6.74 (m, 2 H), 6.54 - 6.61 (m, 1 H), 3.72 (s, 3 H), 3.64 (s, 2 H), 1.68 - 1.87 (m, 2 H). 347 WO 2009/016498 PCT/IB2008/002046 Step 2 : Preparation of N-(3-fluoro-5-methoxybenzvl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F 0 N NH N OH O N (3-Fluoro-5-methoxyphenyl)methanamine was reacted according to procedures described in 5 Example 307 to afford the title compound (22 mg). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.27 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.06 (s, 1 H), 6.55 - 6.84 (m, 3 H), 4.63 (d, J=7.3 Hz, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 4.29 (t, J=5.1 Hz, 1 H), 3.60 - 3.80 (m, 3 H), 2.66 (s, 3 H), 2.40 - 2.54 (m, 1 H), 1.88 - 2.06 (m, 1 H), 1.72 (d, J=11.0 Hz, 2 H), 1.60 (d, J=11.0 Hz, 2 H), 1.27 (d, J=11.7 Hz, 1 H), 0.96 - 1.14 (m, 2 H), 0.74 - 0.98 (m, 2 H). 10 Example 321 N-((2,3-Dihydrobenzofuran-6-yl)methyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexy)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide O N N , --- N NH - OH O N Step 1: Preparation of (2,3-dihydrobenzofuran-5-vl)methanamine 15 x NH 2 To a suspension of lithium aluminum hydride (0.38 mL, 2.0 M in tetrahydrofuran) was added dropwise a solution of 2,3-dihydrobenzofuran-6-carbonitrile (0.10 g, 0.61 mmol) in tetrahydrofuran (2.0 mL) at 0 *C. The reaction was allowed to warm to room temperature and then was heated at 70 *C for 3 hours. A saturated solution of sodium sulfate (1-2 mL) was added dropwise until hydrogen gas 20 evolution ceased. The precipitate was filtered off and the filtrate was diluted with ethyl acetate (10 mL). The organic layer was separated, washed with water (2 x 5 mL) followed by brine (5 mL), dried over sodium sulfate, and concentrated. The residue was taken up in acetonitrile and filtered through a Celite T" pad. The filtrate was concentrated to afford the title compound as an oil (65 mg, 61%). LC/MS (5-100% CH 3
CN/H
2 0, 5 min) 0.73 min, m/z 150 (M+H). 348 WO 2009/016498 PCT/IB2008/002046 Step 2 : Preparation of N-((2,3-dihydrobenzofuran-6-yl)methyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide NN NH - OH 0 N (2,3-Dihydrobenzofuran-5-yl)methanamine was reacted according to procedures described in 5 Example 307 to afford the title compound (33 mg). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.13 (t, J=6.6 Hz, 1 H), 8.39 (s, 1 H), 8.04 (s, 1 H), 7.13 (d, J=7.3 Hz, 1 H), 6.61 - 6.84 (m, 3 H), 4.63 (d, J=7.3 Hz, 2 H), 4.37 - 4.56 (m, 4 H), 4.29 (t, J=5.1 Hz, 1 H), 3.00 - 3.19 (m, 1 H), 2.64 (s, 3 H), 2.46 - 2.58 (m, 2 H), 1.84 - 2.04 (m, 1 H), 1.72 (d, J=10.3 Hz, 2 H), 1.60 (d, J=1 1.0 Hz, 2 H), 1.29 (d, J=5.9 Hz, 1 H), 0.93 - 1.18 (m, 2 H), 0.72 - 0.97 (m, 2 H). 10 Example 322 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide \ - N , NH N OH O N (3-Methoxyphenyl)methanamine was reacted according to procedures described in Example 15 307 to afford the title compound (46 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.261 min., m/z 451 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.23 (m, 1 H), 8.39 (s, 1 H), 8.05 (s, 1 H), 7.12 - 7.28 (m, 1 H), 6.94 - 6.84 (m, 2 H), 6.82 - 6.72 (m, 1 H), 4.63 (d, J=7.0 Hz, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.70 (s, 3 H), 3.21 - 3.08 (m, 2 H), 2.64 (s, 3 H), 2.04 - 1.81 (m, 1 H), 1.78 1.50 (m, 4 H), 1.43 - 1.16 (m), 1.15 - 0.71 (m, 4 H). 20 Example 323 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide F 0 N NH -N OH O N 4-Fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the 25 synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 349 WO 2009/016498 PCT/IB2008/002046 yl)pyrimidine-4-carboxamide, Example 1) (133 mg, 0.857 mmol) and diisopropylethylamine (0.5 mL, 0.308 mmol) was added to a solution of 4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinic acid (prepared as described in step 2 of the synthesis of N-((2,3 dihydrobenzofuran-5-yl)methyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 5 methylpicolinamide, Example 307) (102 mg, 0.308 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 10 minutes. (Benzotriazol-1-yloxy) dimethylaminomethylene]dimethylammonium tetrafluoroborate (254 mg, 0.79 mmol) was added and stirring continued for 30 minutes. The reaction mixture was concentrated and purified by reverse phase preparative HPLC followed by neutralization using a carbonate column to afford the title 10 compound (50 mg, 28%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.331 min., m/z 469 (M+H). IH NMR (400 MHz, CDCl) ( ppm 0.91 - 1.04 (m, 2 H), 1.05 - 1.19 (m, 2 H), 1.39 - 1.54 (m, 1 H), 1.66 - 1.90 (m, 4 H), 2.00 - 2.14 (m, 1 H), 2.61 (s, 3 H), 3.38 - 3.48 (m, 3 H), 3.86 (s, 3 H), 4.52 (d, J=7.0 Hz, 2 H), 4.62 (d, J=6.4 Hz, 2 H), 6.85 - 6.92 (m, 1 H), 6.94 - 7.06 (m, 2 H), 8.03 (d, J=1.3 Hz, 1 H), 8.42 (t, J=6.2 Hz, 1 H), 8.70 (s, 1 H). 15 Example 324 N-(3-Bromobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide BrNH N' OH 0 N Triethylamine (0.16 mL, 1.18 mmol) and 3-bromobenzylamine hydrochloride (55 mg, 0.245 20 mmol) were added to a solution of 4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinic acid (prepared as described in step 2 of the synthesis of N-((2,3 dihydrobenzofuran-5-yl)methyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 307) (65 mg, 0.196 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 30 minutes. O-(1 H-Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium 25 hexafluorophosphate (186 mg, 0.49 mmol) was added and stirring continued overnight. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound (1.5 mg, 1.5%). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 1.13 - 1.31 (m, 4 H), 1.74 - 1.98 (m, 3 H), 2.01 - 2.23 (m, 3 H), 2.64 (s, 2 H), 4.35 (d, J=6.7 Hz, 2 H,) 4.56 (d, J=7.0 Hz, 2 H), 4.66 (d, J=6.2 Hz, 2 H), 7.14 - 7.27 (m, 1 H), 7.30 (d, J=7.8 Hz, 1 H), 7.34 - 7.44 (m, 2 H), 7.44 - 7.57 (m, 2 H), 8.02 (d, J=8.6 Hz, 1 H), 8.07 (d, 30 J=1.1 Hz, 1 H), 8.52 (t, J=6.2 Hz, 1 H), 8.71 (s, 1 H). Example 325 N-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl) methyl)-2H-tetrazol 5-yi)-6-methylpicolinamide 350 WO 2009/016498 PCT/IB2008/002046 HO ON N' N 0 N 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (137 mg, 0.362 mmol) was added to a mixture of 4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinic acid (prepared as described in step 2 of the synthesis of N-((2,3-dihydrobenzofuran 5 5-yl)methyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 307) (100 mg, 0.302 mmol), 2-(3-(aminomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of N-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 13) (60.55 mg, 0.362 mmol), and triethylamine (0.09 mL, 0.664 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at room 10 temperature for 18 hours and then purified by reverse phase preparative HPLC. Fractions containing the desired product were combined, passed through a carbonate cartridge to neutralize, and concentrated to afford the title compound as a white solid (32 mg, 22%). MS (ES+) m/z 481 (M+H). 'H NMR (400 MHz, CDC13) 6 ppm 0.89 - 1.32 (m, 4 H), 1.40 - 1.58 (m, 1 H), 1.65 - 2.01 (m, 6 H), 1.99 2.19 (m, 1 H), 2.64 (s, 3 H), 3.47 (d, J=6.18 Hz, 2 H), 3.89 - 4.01 (m, 2 H), 4.03 - 4.15 (m, 2 H), 4.54 15 (d, J=6.98 Hz, 2 H), 4.67 (d, J=6.18 Hz, 2 H), 6.79 - 6.89 (m, 1 H), 6.91 - 7.04 (m, 2 H), 7.21 - 7.34 (m, 1 H), 8.06 (s, 1 H), 8.48 (t, J=5.77 Hz, 1 H), 8.73 (s, 1 H). Example 326 N-(3-Propoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide N' ONH N OH O N 20 Step 1: Preparation of 3-propoxybenzonitrile OOaCN A mixture of potassium hydroxide (18.8 g, 85 %, crushed) in dimethylsulfoxide (80 mL) was stirred for 5 minutes at ambient temperature. To this white slurry was added 3-cyanophenol (10.0 g) 25 and iodopropane (28.5 g). The mixture was stirred for 2.5 hours at room temperature. The reaction mixture was poured into 1 L of ice water and then extracted with dichloromethane (5 x 300 mL). The combined organic layers were washed with water (5 x 500 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded the title compound (13.23 g, 97.8%). 351 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of (3-propoxyphenyl)methanamine O NH 2 3-Propoxybenzonitrile (13.2 g) was dissolved in absolute ethanol (100 mL) and the solution was sparged with nitrogen gas. Palladium on carbon catalyst (4.0 g) was added and the mixture was 5 shaken under hydrogen gas for 2 hours. The mixture was sparged, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/methanol/NH 4 0H, 97/3/0.3; 94/6/0.6; 90/10/1) to afford the title compound (8.47 g). Step 3: Preparation of N-(3-propoxybenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide N N N ONH N OH 0 N 10 (3-Propoxyphenyl)methanamine (59.8 mg, 0.362 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (44mg, 30%). MS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 0.91 - 1.06 (m, 5 H), 1.08 - 1.25 (m, 3 H), 1.43 - 1.56 (m, 1 H), 1.71 - 1.91 (m, 6 H), 2.04 - 2.18 (m, 1 H), 2.66 (s, 3 H), 3.43 - 3.50 (m, 2 H), 3.93 (t, J=6.58 Hz, 2 15 H), 4.55 (d, J=7.25 Hz, 2 H), 4.68 (d, J=6.18 Hz, 2 H), 6.84 (dd, J=8.19, 2.28 Hz, 1 H), 6.91 - 7.01 (m, 2 H), 7.22 - 7.32 (m, 1 H), 8.07 (d, J=1.34 Hz, 1 H), 8.49 (t, J=5.91 Hz, 1 H), 8.75 (s, 1 H). Example 327 N-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-(2-(((trans)-4 (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 0 NH N OH 0 N 20 (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methanamine (37.4 mg, 0.226 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (3.2 mg, 9%). MS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 0.92 - 1.32 (m, 8 H), 1.71 - 1.93 (m, 4 H), 2.02 - 2.17 (m, 1 H), 2.70 (s, 2 H), 3.48 (d, J=6.18 Hz, 2 H), 4.26 (s, 3 H), 4.58 (dd, J=17.19, 25 6.44 Hz, 4 H), 6.80 - 6.95 (m, 3 H), 8.10 (d, J=1.34 Hz, 1 H), 8.62 (br. s., 1 H), 8.77 (s, 1 H). 352 WO 2009/016498 PCT/IB2008/002046 Example 328 4-(2-(((trans)-4-(Hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-N-((2-methoxypyridin-4 yl)methyl)-6-methylpicolinamide ONH N- OH 0 N 5 (2-Methoxypyridin-4-yl)methanamine (39.5 mg, 0.226 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (5.4 mg, 7%). MS (ES+) m/z 452 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 0.93 - 1.30 (m, 5 H), 1.41 - 1.56 (m, 1 H), 1.76 (d, J=12.89 Hz, 2 H), 1.87 (d, J=10.47 Hz, 2 H), 2.04 - 2.17 (m, 1 H), 2.68 (s, 3 H), 3,48 (d, J=6.18 Hz, 2 H), 3.96 (s, 3 H), 4.55 (d, J=6.98 Hz, 2 H), 4.69 (d, J=6.18 Hz, 2 H), 6.77 (s, 1 H), 6.92 (d, J=5.10 Hz, 10 1 H), 8.10 (s, 1 H), 8.15 (d, J=5.37 Hz, 1 H), 8.54 (t, J=6.31 Hz, 1 H), 8.73 (s, 1 H). Example 329 N-(4-Fluorobenzyl)-4-(2-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F NH - OH 0 N 15 A mixture of N-(4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 1 of the synthesis of (trans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 255) (50 mg, 0.16 mmol), polymer supported triphenylphosphine (186 mg, 0.4 mmol), and trans-cyclohexane-1,4 dimethanol (46 mg, 0.32 mmol) in tetrahydrofuran (3 mL) was cooled in an ice bath and di-tert-butyl 20 azodicarboxylate (74 mg, 0.32 mmol) was added, The mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was acidified with trifluoroacetic acid and filtered. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC. The product was dissolved in dichloromethane and passed through a carbonate resin column. The filtrate was concentrated to afford the title compound as a white solid (36.7 mg). MS (ES+) m/z 25 439 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.35 (t, J=6.4 Hz, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 7.39 (dd, J=8.4, 5.7 Hz, 2 H), 7.16 (t, J=8.9 Hz, 2 H), 4.67 (d, J=7.0 Hz, 2 H), 4.52 (d, J=6.3 Hz, 2 H), 4.37 (t, J=5.3 Hz, 1 H), 3.19 (t, J=5.7 Hz, 2 H), 2,68 (s, 3 H), 1.91 - 2.02 (m, 1 H), 1.71 - 1.78 (m, 2 H), 1.58 - 1.64 (m, 2 H), 1.24 - 1.37 (m, 1 H), 1.02 - 1.14 (m, 2 H), 0.81 - 0.94 (m, 2 H). 353 WO 2009/016498 PCT/IB2008/002046 Example 330 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide 'N.N NH N OH 0 N 5 N-(3-Methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (100 mg, 0.31 mmol), polymer supported triphenylphosphine (287 mg, 0.62mmol), and cis-cyclohexane-1,4-dimethanol (89 mg, 0.62 mmol) (Kuroda, C.; Murase, A.; Suzuki, hours.; Endo, T.; Anzai, S. Bull Chem. Soc. Jpn. 1998, 71, 1639-1647.) were suspended in 10 tetrahydrofuran (10 mL). The mixture was cooled toO 0C. Di-tert-butyl azodicarboxylate (142 mg, 0.62 mmol) was added. The mixture was allowed to warm to room temperature and stir for 36 hours. The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2) to afford the title compound as an oil (62 mg, 45%). MS (ES+) m/z 351 (M+H). 1 H NMR 15 (400 MHz, DMSO-de) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.42 (d, J=0.9 Hz, 1 H), 8.08 (d, J=1.1 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 - 6.90 (m, 2 H), 6.82 (ddd, J=8.2, 2.5, 0.9 Hz, 1 H), 4.76 (d, J=7.7 Hz, 2 H), 4.51 (d, J=6.4 Hz, 2 H), 4.37 (t, J=5.4 Hz, 1 H), 3.73 (s, 3 H), 3.33 (dd, J=6.4, 5.5 Hz, 2 H), 2.68 (s, 3 H), 2.31 - 2.21 (m, 1 H), 1.65 - 1.27 (m, 9 H). Example 331 20 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)methyl)-2H-tetrazo-5-yl) 6-methylpicolinamide ~~N NH - OH O N A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 25 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (105 mg), 2-((trans)-4 (hydroxymethyl)cyclohexyl)propan-2-ol (Aust. J. Chem. 1993, 46, 1869-1879) (98.7 mg), and polymer supported triphenylphosphine (740 mg) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice bath. Di-tert-butyl azodicarboxylate (126 mg) was added and the mixture was placed in an ultrasonic bath for 30 minutes. The reaction mixture was filtered and the resin was washed with tetrahydrofuran 30 and methanol. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20). The fractions containing product were 354 WO 2009/016498 PCT/IB2008/002046 concentrated. The aqueous residue was made basic with 5% aqueous sodium bicarbonate (3 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound (118 mg). MS (ES+) m/z 479 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 8.07 (s, 1 H), 5 7.24 (t, J=8.1 Hz, 1 H), 6.90 - 6.94 (m, 2 H), 6.82 (d, J=7.7 Hz, 1 H), 4.65 (d, J=7.0 Hz, 2 H), 4.51 (d, J=6.6 Hz, 2 H), 3.94 (s, 1 H), 3.73 (s, 3 H), 2.67 (s, 3 H), 1.95 (s, 1 H), 1.80 (d, J=12.1 Hz, 2 H), 1.65 (d, J=11.3 Hz, 2 H), 1.13 (d, J=8.1 Hz, 1 H), 0.97 - 1.07 (m, 10 H) Example 332 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)methyl)-2H 10 tetrazol-5-yl)-6-methylpicolinamide F o N N -N NH - OH 0 N The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-(((trans)-4 (2-hydroxypropan-2-yl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 331) by reaction with 15 N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide, Example 170) and afforded 53.8 mg as an oil. MS (ES+) m/z 497 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.16 (d, J=8.4 Hz, 1 H), 7.11 (dd, J=11.5, 8.2 Hz, 1 H), 6.85 - 6.92 (m, 1 H), 4.62 (d, J=6.6 Hz, 2 H), 4.48 20 (d, J=6.2 Hz, 2 H), 3.92 (s, 1 H), 3.80 (s, 3 H), 2.65 (s, 3 H), 1.87 - 1.98 (m, 1 H), 1.78 (d, J=1 1.7 Hz, 2 H), 1.63 (d, J=11.3 Hz, 2 H), 0.90 - 1.23 (m, 11 H). Example 333 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide N HN - NN 25 Step 1: Preparation of 4-(hydroxymethyl)cyclohexanol 355 WO 2009/016498 PCT/IB2008/002046 OH HO 1 A solution of 2M lithium aluminum hydride in tetrahydrofuran (70 mL) was added to diethyl ether (100 mL) in a mechanically stirred 2L flask. A solution of ethyl 4 hydroxycyclohexanecarboxylate (24.92 g) in diethyl ether (100 mL) was added dropwise over 50 5 minutes. The mixture was heated at reflux for 1 hour and then stirred overnight at room temperature. Ethyl acetate (5 mL) was carefully added and the mixture was acidified with 12 N hydrochloric acid (50 mL) with ice bath cooling. The organic layer was decanted and the aqueous layer was extracted with a mixture of tetrahydrofuran (150 mL) and ether (100 mL). The aqueous layer was neutralized with sodium bicarbonate (75 g) and extracted with ethyl acetate (4 x 400 mL). The combined organic 10 layers were dried over magnesium sulfate, filtered and concentrated. The resulting oil was distilled under reduced pressure to afford the title compound as a colorless oil (15.07 g). Step 2: Preparation of N-(3-methoxybenzvl)-4-(2-(((trans)-4-hydroxvcvclohexvl)methVl)-2H-tetrazol-5 vl)-6-methylpicolinamide HN 0N /2 \ N OH N s \ - NN 15 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (986 mg), 4-(hydroxymethyl)cyclohexanol (614 mg), and polymer supported triphenylphosphine (3.55 g, 7.5 mmol) in tetrahydrofuran (60 mL) was cooled in an ice bath. Di-tert-butylazodicarboxylate (1.046 g) was added and the mixture was placed 20 in an ultrasonic bath for 50 minutes. The mixture was filtered and the resin was washed with tetrahydrofuran. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 35/65 - 55/45). Fractions containing the first eluting isomer were combined and concentrated. The residue was dissolved in dichloromethane and washed with 5% aqueous sodium bicarbonate (3 mL). The organic layer was dried over magnesium sulfate, 25 filtered, and concentrated to afford the title compound (298 mg). MS (ES+) m/z 437 (M+H). IH NMR (400 MHz, DMSO-de) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.87 - 6.92 (m, 2 H), 6.77 - 6.82 (m, 1 H), 4.63 (d, J=7.0 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.52 (s, 1 H), 1.89 - 1.98 (m, 1 H), 1.77 - 1.85 (m, 2 H), 1.53 - 1.61 (m, 2 H), 1.37 (d, J=7.3 Hz, 2 H), 1.03 - 1.17 (m, 2 H). 30 Example 334 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-y)-6 methylpicolinamide 356 WO 2009/016498 PCT/IB2008/002046 N O N" NN OH - N' Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 333 afforded the title compound (520 mg). MS (ES+) m/z 437 (M+H). H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.21 (t, J=8.1 5 Hz, 1 H), 6.87 - 6.92 (m, 2 H), 6.79 (dd, J=8.4, 1.5 Hz, 1 H), 4.65 (d, J=7.0 Hz, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 4.30 (br. s., 1 H), 3.73 (br. s., 1 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.52 (s, 1 H), 2.04 (br. s., 1 H), 1.54 - 1.63 (m, 2 H), 1.27 - 1.48 (m, 5 H). Example 335 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 10 methylpicolinamide F N O N - NN Step 1: Preparation of methyl 4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-vl)-6 methylpicolinate 0 0 / \ N.N ,OH N 12 x 1 - N '-0 15 A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (5.0 g, 28.8 mmol), 4-(hydroxymethyl)cyclohexanol (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4 hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 333) (3.71 g, 28.5 mmol), 20 and polymer supported-triphenylphosphine (21.2 g, 45.6 mmol) in tetrahydrofuran (100 mL) was cool to O 0C in an ice bath. Di-tert-butyl azodicarboxylate (10,5 g, 45.6 mmol) was added and stirring was continued for 60 minutes in an ice bath. The mixture was allowed to warm to room temperature and stir overnight, The reaction mixture was filtered and the resin was washed with tetrahydrofuran. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC. Isolation 25 of the first eluting isomer afforded the title compound as a clear, light yellow colored oil (1.48 g). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.22 min., m/z 332 (M+H). 'H NMR (500 MHz, DMSO-d) 6 ppm 1.04 - 1.16 (m, 3 H), 1.57 (d, J=7.07 Hz, 2 H), 1.78 - 1.84 (m, 2 H), 1.89 - 1.97 (m, 1 H), 2.63 (s, 3 357 WO 2009/016498 PCT/IB2008/002046 H), 3.29 - 3.36 (m, 1 H), 3.91 (s, 3 H), 4.63 (d, J=7.07 Hz, 2 H), 4.70 (d, J=7.07 Hz, 1 H), 8.08 (d, J=1.63 Hz, 1 H), 8.36 (d, J=11.36 Hz, 1 H). Step 2: Preparation of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F 0 F - HN_ / \ NN \OH - N 5 Diisopropylethylamine (77.9 mg, 0.603 mmol) and (4-fluoro-3-methylphenyl)methanamine (125.9 mg, 0.905 mmol) were added to a solution of methyl 4-(2-(((trans)-4-hydroxycyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinate (100 mg, 0.301 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred for 30 minutes and then heated to 60 *C overnight. The reaction mixture was 10 purified by reverse-phase preparative HPLC to afford the title compound (18.5 mg, 12%). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.09 (t, J=10.25 Hz, 3 H), 1.57 (s, 2 H), 1.79 (s, 2 H), 1.93 (s, 1 H), 2.19 (s, 2 H), 2.65 (s, 2 H), 4.46 (d, J=6.59 Hz, 2 H), 4.63 (d, J=6.59 Hz, 2 H), 6.99 - 7.09 (m, 1 H), 7.12 7.28 (m, 2 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.21 (t, J=6.59 Hz, 1 H). Example 336 15 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F 0 / \ N N \O H N Step 1: Preparation of methyl 4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinate 0 0 N / 20 Isolation of the second eluting isomer from reverse phase preparative HPLC of the reaction mixture obtained in step 1 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4 hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 335) afforded the title compound as a clear, light yellow colored oil (2.41 g). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.34 25 min., m/z 332 (M+H), 1H NMR (500 MHz, DMSO-d) 6 ppm 1.29 - 1.35 (m, 2 H), 1.37 - 1.47 (m, 3 H), 1.60 (dd, J=9.65, 3.67 Hz, 2 H), 1.89 - 2.10 (m, 1 H), 2.64 (s, 3 H), 3.75 (br. s., 1 H), 3.91 (s, 3 H), 4.67 (d, J=7.07 Hz, 2 H), 4.74 (d, J=7.07 Hz, 1 H), 8.11 (s, 1 H), 8.39 (s, 1 H). 358 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-methylbenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F N /~ \ NaN ,\OH Nx Diisopropylethylamine (0.5 mL, 0.287 mmol) and (4-fluoro-3-methylphenyl)methanamine (41.7 5 mg, 0.30 mmol) were added to a solution of methyl 4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinate (25 mg, 0.075 mmol) in N,N-dimethylacetamide (2 mL). The mixture was stirred for 30 minutes and then heated to 60 *C overnight. The reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound (21.5 mg, 65%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.09 (t, J=10.25 Hz, 4 H), 1.57 (s, 2 H), 1.79 (s, 2 H), 1.93 (s, 2 H), 2.19 (s, 3 H), 10 2.65 (s, 3 H), 3.27 (s, 1 H), 4.43 - 4.49 (m, 2 H), 7.01 - 7.08 (m, 1 H), 7.14 - 7.21 (m, 1 H), 7.23 (d, J=6.59 Hz, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.21 (t, J=6.22 Hz, 1 H) Example 337 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide FP H\N 0 F HN Cl Nz N '\OH IN x2 1 N N 15 The title compound (18.7 mg, 13%) was prepared in a similar manner to N-(4-fluoro-3 methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 335) by reaction with (3-chloro-4-fluorophenyl)methanamine. 'H NMR (400 MHz, DMSO-de) 6 ppm 1.09 (t, J=9.88 Hz, 5 H), 1.57 (s, 2 H), 1.79 (s, 2 H), 1.91 (d, J=13.91 Hz, 2 H), 2.66 (s, 3 H), 20 4.43 - 4.53 (m, 3 H), 4.63 (d, J=6.59 Hz, 2 H), 7.34 (d, J=7.32 Hz, 2 H), 7.53 (d, J=7.32 Hz, 1 H), 8.05 (s, 1 H), 8.39 (s, 1 H), 9.34 (t, J=6.22 Hz, 1 H). Example 338 N-(3-Chloro-4-fluorobenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F 0 F- HN 0 Cl / NZN OOH N x - - NN 25 The title compound (18.8 mg, 55%) was prepared in a similar manner to N-(4-fluoro-3 methylbenzyl)-4-(2-(((cis)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 359 WO 2009/016498 PCT/IB2008/002046 (Example 336) by reaction with (3-chloro-4-fluorophenyl)methanamine. 'H NMR (400 MHz, DMSO-d) 6 ppm 1.01 - 1.18 (m, 4 H), 1.57 (s, 3 H), 1.79 (s, 2 H), 1.91 (d, J=13.91 Hz, 1 H), 2.66 (s, 3 H), 4.43 4.54 (m, 3 H), 4.63 (d, J=6.59 Hz, 2 H), 7.34 (d, J=7.32 Hz, 2 H), 7.53 (d, J=8.05 Hz, 1 H), 8.05 (s, 1 H), 8.39 (s, 1 H), 9.34 (t, J=6.22 Hz, 1 H) 5 Example 339 N-(3-Ethoxybenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide N O 0 N NZN OH N - N'N The title compound (18.5 mg, 13%) was prepared in a similar manner to N-(4-fluoro-3 10 methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 335) by reaction with (3-ethoxyphenyl)methanamine (prepared as described in step 2 of the synthesis of N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide, Example 180). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.09 (t, J=9.88 Hz, 5 H), 1.28 (t, J=6.95 Hz, 3 H), 1.57 (s, 2 H), 1.79 (s, 2 H), 1.93 (s, 1 H), 2.65 (s, 3 H), 3.27 (s, 1 H), 3.97 15 (q, J=6.59 Hz, 2 H), 4.41 - 4.53 (m, 2 H), 4.63 (d, J=6.59 Hz, 2 H), 6.78 (d, J=8.05 Hz, 1 H), 6.87 (s, 2 H), 7.20 (t, J=8.05 Hz, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.18 (t, J=6.59 Hz, 1 H) Example 340 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F NO F- HN 0 0 / N '\OH N
-
N 20 The title compound (20.9 mg, 15%) was prepared in a similar manner to N-(4-fluoro-3 methylbenzyl)-4-(2-(((trans)-4-hydroxycyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 335) by reaction with 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H 25 tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1). 1 H NMR (400 MHz, DMSO-d) 6 ppm 1.31 (d, J=8.78 Hz, 2 H), 1.43 (t, J=10.25 Hz, 3 H), 1.59 (dd, J=10.25, 4.39 Hz, 2 H), 2.05 (s, 1 H), 2.51 (s, 1 H), 2.65 (s, 3 H), 3.72 (d, J=10.25 Hz, 1 H), 3.80 (s, 3 H), 4.27 (d, J=2.93 Hz, 1 H), 4.48 (d, J=6.59 Hz, 2 H), 4.65 (d, J=7.32 Hz, 2 H), 6.89 (s, 1 H), 7.07 - 7.13 (m, 1 H), 7.13 - 7.19 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.17 - 9.25 (m, 1 H). 360 WO 2009/016498 PCT/IB2008/002046 Example 341 rac-N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3-oxocyclopentyl)methyl)-2H-tetrazol-5 yl)picolinamide F -N" 0O -- N -o N--- N'N 5 Step 1: Preparation of (3,3-dimethoxvcvclopentyl)methanol 0 A solution of methyl 3,3-dimethoxycyclopentanecarboxylate (Tetrahedron 1977, 33, 1113) (6.22 g) in anhydrous tetrahydrofuran (60 mL) was added dropwise to a solution of 2 M lithium aluminum hydride (20 mL) in anhydrous tetrahydrofuran (240 mL) and the mixture was heated at 40 10 *C for 18 hours. The reaction mixture was cooled in an ice bath and water (7 mL) was added slowly, followed by 10% aqueous sodium hydroxide (2.0 mL). The mixture was heated to 40 *C for an hour. The mixture was filtered through a pad of neutral alumina and rinsed with tetrahydrofuran. The filtrate was concentrated to afford the title compound as an oil (4.77 g). 'H NMR (400 MHz, CDC13) 6 ppm 3.47 - 3.56 (m, 2 H), 3.18 (s, 3 H), 3.18 (s, 3 H), 2.19 - 2.29 (m, 1 H), 1.97 (dd, J=13.2, 8.9 Hz, 1 H), 15 1.92 (s, 1 H), 1.72 - 1.84 (m, 3 H), 1.51 - 1.58 (m, 1 H), 1.36 - 1.47 (m, 1 H). Step 2: Preparation of rac-N-(4-fluoro-3-methoxvbenzvl)-6-methyl-4-(2-((3-oxocyclopentyl)methyl)-2H tetrazol-5-yl)picolinamide F N 0 -O NN Nx -o N~- N'N A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared 20 as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (500 mg), (3,3 dimethoxycyclopentyl)methanol (350 mg), polymer support triphenylphosphine (1.388 g, 3.0 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled in an ice bath. Di-tert-butylazodicarboxylate (403 mg) was added and the mixture was placed in an ultrasonic bath for one hour. After standing overnight, 25 the mixture was filtered and the resin was washed with tetrahydrofuran and methanol. The filtrate was acidified with trifluoroacetic acid and concentrated. The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 75/25). The product containing fractions were concentrated. The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over magnesium 361 WO 2009/016498 PCT/IB2008/002046 sulfate, filtered and concentrated to afford the title compound (435 mg). MS (ES+) m/z 439 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.09 - 7.21 (m, 2 H), 6.90 (s, 1 H), 4.91 (d, J=7.3 Hz, 2 H), 4.50 (d, J=6.2 Hz, 2 H), 3.82 (s, 3 H), 2.88 - 2.97 (m, 1 H), 2.68 (s, 3 H), 2.27 - 2.37 (m, 1 H), 2.18 - 2.24 (m, 2 H), 1.99 - 2.17 (m, 2 H), 1.67 - 1.77 (m, 1 H). 5 Example 342 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3R*)-3-hydroxycyclopentyl)methyl)-2H-tetrazol-5 yi)-6-methylpicolinamide
F
7 P \ 0 P F0 N O O -O N N x. A 2 M solution of lithium aluminum hydride in tetrahydrofuran (0.20 mL) was added to a cooled 10 solution (ice/acetone bath) of rac-N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3 oxocyclopentyl)methyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 341) (272 mg) in anhydrous tetrahydrofuran (5.0 mL) under nitrogen. The mixture was allowed to stir for 5 minutes and was then quenched with methanol (1 mL). The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 40/60 - 60/40). 15 Fractions containing the first eluting isomer were combined and concentrated. The aqueous residue was extracted with dichloromethane (3 x 5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (83 mg). MS (ES+) m/z 441 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.23 (t, J=5.9 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.15 - 7.20 (m, 1 H), 7.09 - 7.15 (m, 1 H), 6.86 - 6.93 (m, 1 H), 4.73 (d, J=7.3 Hz, 2 H), 4.50 (d, J=6.2 Hz, 2 H), 4.43 (s, 1 20 H), 4.16 (s, 1 H), 3.82 (s, 3 H), 2.75 - 2.83 (m, 1 H), 2.67 (s, 3 H), 1.77 - 1.86 (m, 2 H), 1.62 (d, J=6.6 Hz, 1 H), 1.43 - 1.52 (m, 2 H), 1.28 - 1.38 (m, 1 H). Example 343 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3S*)-3-hydroxycyclopentyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide F P\N00H -N OH -O N a \ NN - NN 25 Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 342 afforded the title compound as a white solid (122 mg). MS(ES+) m/z 441 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.23 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.07 (s, 1 H), 7.15 - 7.20 (m, 1 H), 7.10 - 7.15 (m, 1 H), 6.87 - 6.93 (m, 1 H), 4.78 (d, J=7.3 Hz, 2 H), 4.56 (d, 30 J=3.7 Hz, 1 H), 4.50 (d, J=6.2 Hz, 2 H), 4.10 - 4.16 (m, 1 H), 3.82 (s, 3 H), 2.67 (s, 3 H), 2.55 - 2.62 (m, 1 H), 1.86 - 1.94 (m, 1 H), 1.62 - 1.70 (m, 2 H), 1.52 - 1.62 (m, 2 H), 1.31 - 1.38 (m, 1 H). 362 WO 2009/016498 PCT/IB2008/002046 Example 344 N-(3-Methoxybenzyl)-4-(2-(((cis)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazo-5 yl)-6-methylpicolinamide N - N N I 5 Step 1: Preparation of 4-(2-(1,4-dioxaspiro[4.5]dec-8-vlmethyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl) 6-methylpyridine-2-carboxamide 0 -NO -O H NzN 0 N -- N' 1,4-Dioxaspiro[4.5]dec-8-ylmethy 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-6-(2-(((trans)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl) 10 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 28) (1.4 g, 4.3 mmol) is added to a mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide, Example 153) (1.39 g, 4.3 mmol) and triethylamine (434 mg) in anhydrous N,N-dimethylacetamide (2 mL). The mixture was stirred at 85 0C for 64 hours. The reaction mixture is 15 purified by reverse phase preparative HPLC to afford the title compound as an oil (1.7 g). Step 2: Preparation of N-(3-methoxybenzvl)-6-methyl-4-(2-((4-oxocyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide - N O -O H NaN 0 N x N N - N'N Formic acid (96%, 20 mL) was added to a solution of 4-(2-(1,4-dioxaspiro[4.5]dec-8-ylmethyl) 20 2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-6-methylpyridine-2-carboxamide (1.6 g, 3.3 mmol) in tetrahydrofuran (13 mL) and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated and the residue is dissolved in dichloromethane. The mixture was washed with saturated aqueous sodium bicarbonate solution, The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as a white solid (1.6 g). 363 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-methoxybenzyl)-6-methyl-4-(2- (1-oxaspiro[2. 5loct-6-ylmethyl)-2H-tetrazol 5-yl)pyridine-2-carboxamide 0 N -O H 0 N I - NN A solution of N-(3-methoxybenzyl)-6-methyl-4-(2-((4-oxocyclohexyl)methyl)-2H-tetrazol-5 5 yl)picolinamide (445 mg, 1.0 mmol) in anhydrous dimethylsulfoxide (4 mL) was added to a solid mixture of trimethylsulfoxonium iodide (445 mg, 2.0 mmol) and potassium t-butoxide (225 mg, 2.0 mmol). The mixture was allowed to stir at room temperature for 30 minutes. Water (25 mL) was then added and the slurry was stirred at room temperature for 20 minutes. The resulting precipitate was filtered, washed with water and dried under vacuum to afford the title compound (266 mg) 10 Step 4: Preparation of N-(3-methoxybenzyl)-4-(2-(((cis)-4-hydroxy-4 (hydroxymethyl)cyclohexyl')methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide 0 -NO -O H N OH I N N OH N I - N'NN, Perchloric acid (70%, 0.4 mL) was added to N-(3-methoxybenzyl)-6-methyl-4-(2-(1 oxaspiro[2.5]oct-6-ylmethyl)-2H-tetrazol-5-yl)pyridine-2-carboxamide (260 mg, 0.58 mmol) in a mixture 15 of tetrahydrofuran (4 ml) and water (1.2 mL). The mixture was allowed to stir at room temperature for 3.5 hours. The reaction mixture was purified by reverse phase preparative HPLC followed by elution through a carbonate resin column. The resulting mixture of isomers were separated by supercritical fluid chiral chromatography (OJ-H column, 30 x 250 mm, 20% 2-propanol, 70 mL/min) and the first eluting isomer was isolated to afford the title compound as a white solid (32 mg). MS (ES+) m/z 467 20 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.88 - 6.92 (m, 2 H), 6.80 (d, J=8.8 Hz, 1 H), 4.64 (d, J=7.0 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 4.39 (t, J=5.3 Hz, 1 H), 3.80 (s, 1 H), 3.71 (s, 3 H), 3.10 (d, J=5.5 Hz, 2 H), 2.65 (s, 3 H), 1.87 - 1.97 (m, 1 H), 1.25 - 1.49 (m, 8 H). Example 345 25 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)-6-methylpicolinamide 364 WO 2009/016498 PCT/IB2008/002046 - N -O H N N'N OH OH N - N'N Isolation of the second eluting isomer by supercritical fluid chiral chromatography (OJ-H column, 30 x 250 mm, 20% 2-propanol, 70 mL/min) from the reaction mixture described in Example 344 afforded the title compound as a white solid (54 mg). MS (ES+) m/z 467 (M+H). 5 Example 346 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide O HO - HN ON S - NN Step 1: Preparation of ((trans)-4-(hydroxymethyl)cyclohexyl)methyI 4-methylbenzenesulfonate 0 10 HO O 4-Methylbenzenesulfonyl chloride (19.0 g, 100 mmol) was added to a solution of trans-1,4 cyclohexane dimethanol (14.4 g, 100 mmol) in anhydrous pyridine (50 mL) cooled in an ice bath. The mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was diluted with ether (300 mL), poured into water (400 mL), and filtered. The separated aqueous 15 layer was further extracted with ether (2 x 200 mL). The combined organic layers were washed with water (200 mL), 1 N hydrochloric acid (2 x 200 mL), water (200 mL), and saturated aqueous sodium bicarbonate solution (200 mL). The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as an oil (14.8 g). Step 2: Preparation of methyl 6-methyl-4-(2-(((trans)-4-((tosyloxy)methvl)cyclohexyl)methyl)-2H 20 tetrazol-5-yl)picolinate 0 0 / \ N O N - N.N ,S 0 In a 100 ml round-bottomed flask under nitrogen at room temperature, methyl 6-methyl-4-(2H tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (0.835 mg, 365 WO 2009/016498 PCT/IB2008/002046 3.81 mmol) was combined with ((trans)-4-(hydroxymethyl)cyclohexyl)methyl 4 methylbenzenesulfonate (1.25 g, 4.19 mmol), polymer supported-triphenylphosphine (4.87 g, 10.5 mmol) and tetrahydrofuran (30 mL). The mixture was cool to 0 *C in a dry ice bath for 20 minutes and di-tert-butyl azodicarboxylate (1.75 g, 7.62 mmol) was added. The mixture was stirred in a dry ice 5 bath for 1 hour and then allowed to warm to room temperature and stir overnight. The reaction mixture was filtered and the resin was washed with tetrahydrofuran. The residue was purified by reverse phase preparative HPLC to afford the title compound (1.295 g). LC/MS (5%-95%
CH
3
CN/H
2 0, 5 min.) 3.565 min., m/z 500 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 0.88 - 1.18 (m, 3 H), 1.55 - 1.82 (m, 4 H), 1.95 - 2.12 (m, 1 H), 2.38 - 2.46 (m, 3 H), 2.91 (s, 3 H), 3.79 (d, J=6.18 Hz, 2 10 H), 4.04 (s, 3 H), 4.56 (d, J=7.25 Hz, 2 H), 7.31 (d, J=8.06 Hz, 2 H), 7.67 - 7.79 (m, 2 H), 8.44 (s, 1 H), 8.85 (s, 1 H), 13.80 (s, 2 H). Step 3: Preparation of methyl 6-methyl-4-(2-(((trans)-4-(methylthiomethyl)cvclohexyl)methyl)-2H tetrazol-5-yl)picolinate 0 0 NNNS N~ / -Y - NN 15 Sodium thiomethoxide (0.363 g, 5.18 mmol) was added to a solution of methyl 6-methyl-4-(2 (((trans)-4-((tosyloxy)methyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinate (1.295 g, 2.592 mmol) in dimethylsulfoxide (20 mL) and the mixture was heated at 50 0C for 2 hours. The reaction mixture was passed through a silica plug, eluted with ethyl acetate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound as a clear, light yellow colored oil (0.973 20 g). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.536 min., m/z 376 (M+H). Step 4: Preparation of methyl 6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexvl)methyl)-2H tetrazol-5-vl)picolinate 0 0N N ~ / NN" N I - N N 3-Chloroperoxybenzoic acid (772 mg, 4.47 mmol) was added to a solution of methyl 6-methyl 25 4-(2-(((trans)-4-(methylthiomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinate (381.4 mg, 1.016 mmol) in dichloromethane (10 mL) and the mixture was allowed to stir overnight. A saturated aqueous sodium bicarbonate solution (5 mL) was added. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a clear, colorless oil (415 mg). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.626 min., m/z 408 (M+H). 366 WO 2009/016498 PCT/IB2008/002046 Step 5: Preparation of 6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinic acid 0 HO N NS A solution of lithium hydroxide (1 M, 1 ml, 1.0 mmol) was added to a solution of methyl 6 5 methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinate (414 mg, 1.02 mmol) in tetrahydrofuran (10 mL). The mixture was allowed to stir at room temperature overnight and was then concentrated to afford the title compound. LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 2.090 min., m/z 394 (M+H). 1H NMR (400 MHz, CDC1 3 ) 6 ppm 1.08 - 1.29 (m, 4 H), 1.99 (s, 1 H), 2.00 - 2.17 (m, 4 H), 2.86 - 3.00 (m, 8 H), 4.60 (d, J=6.98 Hz, 2 H), 8.48 (s, 1 H), 8.87 (s, 1 H), 12.53 (br. s., 2 H). 10 Step 6: Preparation of N-(3-(2-hydroxvethoxy)benzVl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl) cyclohexyl)methyl)-2H-tetrazol-5-vl)picolinamide 0 HO HN 0 N N N \\O A mixture of 6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinic acid (50.0 mg, 0.130 mmol), diisopropylethylamine (150 mg, 1.10 mmol), and 2-(3 15 (aminomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of N-(3-(2 hydroxyethoxy)benzyl)-6-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine 4-carboxamide, Example 13) (42.0 mg, 0.250 mmol) in N,N-dimethylformamide (2.0 mL) was stirred for 20 minutes. O-(1H-Benzotriazol-1-yl)-N,N,N',N-tetramethyluronium tetrafluoroborate (102 mg, 0.318 mmol) was added and the mixture was stirred for 3 hours. The reaction mixture was purified by 20 reverse phase preparative HPLC to afford the title compound as the trifluoroacetate salt (38.0 mg, 55% yield). 1H NMR (400 MHz, DMSO-d) 6 ppm 1.05 - 1.16 (m, 14 H), 1.61 (d, J=10.25 Hz, 9 H), 1.90 (d, J=10.98 Hz, 11 H), 2.65 (s, 9 H), 2.90 - 2.96 (m, 10 H), 2.99 (d, J=6.59 Hz, 7 H), 3.67 (d, J=4.39 Hz, 7 H), 3.93 (t, J=5.12 Hz, 8 H), 4.49 (d, J=6.59 Hz, 9 H), 4.64 (d, J=7.32 Hz, 8 H), 6.85 6.93 (m, 6 H). 25 Example 347 N-(3-Hydroxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H tetrazol-5-yl)picolinamide 367 WO 2009/016498 PCT/IB2008/002046 HN HO N S N / I - NN The title compound (49.0 mg, 77%) was prepared in a similar manner to N-(3-(2 hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide (Example 346) by reaction with 3-(aminomethyl)phenol. 'H NMR (400 MHz, DMSO 5 de) 6 ppm 1.05 - 1.16 (m, 17 H), 1.61 (d, J=10.98 Hz, 11 H), 1.82 - 1.93 (m, 14 H), 2.65 (s, 12 H), 2.90 - 2.97 (m, 12 H), 2.99 (d, J=5.86 Hz, 8 H), 4.44 (d, J=6.59 Hz, 10 H), 4.64 (d, J=6.59 Hz, 9 H), 6.70 6.77 (m, 7 H) Example 348 N-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl) 10 2H-tetrazol-5-yl)picolinamide F N Cl NN - NN O The title compound (48.0 mg, 58%) was prepared in a similar manner to N-(3-(2 hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide (Example 346) by reaction with (3-chloro-4-fluorophenyl)methanamine. 1H NMR 15 (400 MHz, DMSO-d 6 ) 6 ppm 1.04 - 1.15 (m, 18 H), 1.61 (d, J=11.71 Hz, 12 H), 1.81 - 1.93 (m, 16 H), 2.66 (s, 13 H), 2.89 - 2.95 (m, 12 H), 2.99 (d, J=5.86 Hz, 9 H), 4.49 (d, J=5.86 Hz, 10 H), 4.64 (d, J=6.59 Hz, 10 H). Example 349 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((trans)-4 20 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide F N O N S - N'N The title compound (76.5.0 mg, 56%) was prepared in a similar manner to N-(3-(2 hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylimethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide (Example 346) by reaction with 4-fluoro-3-methoxybenzylamine hydrochloride 25 (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.08 - 1.16 (m, 12 H), 1.61 (d, J=10.26 Hz, 10 H), 1.82 - 1.93 (m, 12 H), 1.97 (s, 7 368 WO 2009/016498 PCT/IB2008/002046 H), 2.65 (s, 9 H), 2.92 (s, 9 H), 2.99 (d, J=5.86 Hz, 8 H), 3.80 (s, 8 H), 4.48 (d, J=5.86 Hz, 9 H), 4.64 (d, J=5.86 Hz, 8 H), 7.06 - 7.18 (m, 7 H). Example 350 N-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((trans)-4 5 (methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide - N HO N Z"' N O - N N0%:11 The title compound (45.0 mg, 69%) was prepared in a similar manner to N-(3-(2 hydroxyethoxy)benzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol 5-yl)picolinamide (Example 346) by reaction with (3-(aminomethyl)phenyl)methanol. 'H NMR (400 10 MHz, DMSO-d) 6 ppm 1.04 - 1.16 (m, 17 H), 1.61 (d, J=11.71 Hz, 11 H), 1.81 - 1.93 (m, 14 H), 2.65 (s, 12 H), 2.89 - 2.95 (m, 12 H), 2.99 (d, J=5.86 Hz, 8 H), 4.45 (s, 7 H), 4.48 - 4.56 (m, 10 H), 4.64 (d, J=7.32 Hz, 9 H) Example 351 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H-tetrazoI-5-yl)-6 15 methylpicolinamide 0 N,0 - HN 0 N / NH 2 N Step 1: Preparation of tert-butyl ((trans)-4-(hydroxymethvl)cyclohexyl)methvlcarbamate HO wO 0 A solution of trans 4-(tert-butyloxycarbonylamino)methylcyclohexanecarboxylic acid (5.0 g, 19 20 mmol) in a mixture of 1,4-dioxane/tetrahydrofuran (1/1, 20 mL) was added drop wise to a cooled suspension of lithium aluminum hydride (2.1 g, 57 mmol) and the resulting mixture was stirred at room temperature for 15 hours. The excess of lithium aluminum hydride was destroyed by drop wise addition of water (2 mL). The suspension was filtered and the filter cake was washed with tetrahydrofuran (10 mL) and methanol (2 x 10 mL). The filtrate was concentrated in vacuo and 25 extracted with ethyl acetate ( 3 x 15 mL). The combined organic layers were dried with sodium sulfate and concentrated to afford the title compound as a light amber oil which solidified on standing (3.7 g, 80%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 4.79 min, m/z 266 (M+Na). 369 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(3-methoxybenzyl)-4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide HN O 0 N I HN N /N NH 2 N A mixture of tert-butyl ((trans)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (0.75 g, 3.1 5 mmol), N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (0.50 g, 1.5 mmol), and polymer supported-triphenylphosphine (1.85 g, 2.65 mmol) in tetrahydrofuran (25.0 mL) was cooled to 0 *C in an ice bath for 15 minutes. Di tert-butyl azodicarboxylate (755 mg, 3.08 mmol) was added and the mixture was allowed to warm to 10 room temperature and stir for 48 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo. The residue was triturated with diethyl ether and further purified by reverse phase preparative HPLC (10-90% acetonitrile/water) to afford the title compound as a white solid (0.24 g, 52%). LC/MS 15 (5-100% CH 3
CN/H
2 0, 8 min) 4.59 min, m/z 450 (M+H). Example 352 N-(3-Methoxybenzyl)-4-(2-(((trans)-4-(acetamidomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide HN HN 0 N H N / r/ N 0 20 Triethylamine (0.031 ml) and acetyl chloride (0.010 mL) was added to a solution of N-(3 methoxybenzyl)- 4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 351) (0.050 g, 0.010 mmol) in N,N dimethylformamide (1 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 5 mL). The combined 25 organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (19 mg, 39%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.13 - 9.25 (m, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.69 (s, 1 H), 7.17 7.26 (m, 1 H), 6.90 (s, 2 H), 6.80 (d, J=8.05 Hz, 1 H), 4.64 (d, J=6.59 Hz, 2 H), 4.49 (d, J=6.59 Hz, 2 H), 3.71 (s, 3 H), 2.84 (t, J=5.86 Hz, 2 H), 2.65 (s, 3 H), 1.96 (d, J=2.93 Hz, 1 H), 1.76 (s, 3 H), 1.68 (d, 30 J=11.71 Hz, 2 H), 1.60 (d, J=12.45 Hz, 2 H), 1.30 (s, 1 H), 0.98 - 1.12 (m, 2 H), 0.79 - 0.94 (m, 2 H). 370 WO 2009/016498 PCT/IB2008/002046 Example 353 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamidomethyl)cyclohexyl)methyl) 2H-tetrazol-5-yl)picolinamide P-HN O \ HN - NN 0 5 Triethylamine (0.031 ml) and methane sulfonylchloride (0.010 mL) was added to a solution of N-(3-methoxybenzyl)- 4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 351) (0.050 g, 0.010 mmol) in N,N dimethylformamide (1 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 5 mL). The combined 10 organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (15 mg, 28%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.14 - 9.25 (m, 1 H), 8.41 (s, 1 H), 8.06 (s, 2 H), 7.16 - 7.27 (m, 1 H), 6.87 - 6.96 (m, 2 H), 6.80 (d, J=7.32 Hz, 1 H), 4.64 (d, J=7.32 Hz, 2 H), 4.49 (d, J=6.59 Hz, 2 H), 3.71 (s, 3 H), 2.82 (s, 3 H), 2.74 (t, J=6.59 Hz, 2 H), 2.65 (s, 3 H), 1.97 (s, 1 H), 1.75 (d, J=13.18 Hz, 2 15 H), 1.61 (d, J=11.71 Hz, 2 H), 1.34 (s, 1 H), 0.98 - 1.17 (m, 2 H), 0.79 - 0.95 (m, 2 H). Example 354 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide -P HN F NN N
NH
2
-
N C
I
20 Step 1: Preparation of methyl 4-(2-(((trans)-4-((tert-butoxycarbonyl)methyl)cyclohexyl)methyl)-2H tetrazol-5-yl)-6-methylpicolinate 0 00 -- NN A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of 25 the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (1.50g, 6.85 mmol), tert-butyl ((trans)-4 (hydroxymethyl)cyclohexyl)methylcarbamate (prepared as described in step 1 of the synthesis of N-(3 methoxybenzyl)-4-(2-(((trans)-4-(aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 371 WO 2009/016498 PCT/IB2008/002046 methylpicolinamide, Example 351) (3.00 g, 12.3 mmol), and polymer supported-triphenylphosphine (7.78 g, 17.1 mmol) in tetrahydrofuran (150 mL) was cooled to O *C in an ice bath for 15 minutes. Di tert-butyl azodicarboxylate (3.15 g, 13.7 mmol) was added and the mixture was allowed to warm to room temperature and stir for 15 hours. The reaction mixture was filtered and the filtrate was 5 concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate/heptane) to afford the title compound as an beige solid (2.15 g, 71%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.84 min, m/z 445 (M+H). Step 2: Preparation of 4-(2-(((trans)-4-((terd-butoxycarbonvl)methyl)cyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinic acid 0 HO N~ N I N ~ 10 0 An aqueous solution of sodium hydroxide (2.5 N, 5.0 mL) was added to a solution of methyl 4 (2-(((trans)-4-((tert-butoxycarbonyl)methyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinate (0.50 g, 1.1 mmol) in tetrahydrofuran (5 mL) and water (2 mL) and the mixture was stirred at room 15 temperature for 15 hours. The tetrahydrofuran was removed in vacuo and the aqueous residue was acidified with aqueous hydrochloric acid to pH 7. The resulting white solid was filtered and dried to afford the title compound (0.45g, 92%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.10 min, m/z 431 (M+H). Step 3: Preparation of tert-butyl ((trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexyl)methylcarbamate F N O N NI O 20 0 A mixture of 4-(2-(((trans)-4-((tert-butoxycarbonyl)methyl)cyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinic acid ( 0.080 g, 0.19 mmol) and 1-hydroxybenzatriazole (30 mg, 0.22 mmol) in N,N dimethylacetamide (2 mL) was stirred for 5 minutes. Triethylamine (0.028 g, 0.28 mmol), 4-fluoro-3 methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3 25 methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (35 mg, 0.22 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.28 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as solid (100 mg, 95%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.72 min, m/z 568 (M+H). 372 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of N-(4-fluoro-3-methoxybenzVl)-4-(2-(((trans)-4-(aminomethyl)cyclohexvl)methyl) 2H-tetrazol-5-vl)-6-methylpicolinamide hydrochloride F 0 F-P HN 0 N NH2 N A solution of hydrochloric acid in dioxane (4 N, 6.0 mL) was added to a solution of ter-butyl 5 ((trans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cyclohexyl)methylcarbamate (105 mg, 0.185 mmol) in dichloromethane (2 mL) and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated and the residue was triturated with diethyl ether to afford the title compound as the hydrochloride salt (41 mg, 44%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (br. s., 1 H), 8.40 (br. s., 1 H), 8.05 (br. s., 1 H), 7.97 (br. s., 1 10 H), 7.04 - 7.19 (m, 1 H), 6.87 (br. s., 1 H), 4.65 (br. s., 2 H), 4.47 (br. s., 2 H), 3.79 (br. s., 2 H), 3.54 (s, 3 H), 3.35 (br. s., 1 H), 2.65 (br. s., 3 H), 2.59 (br. s., 1 H), 1.98 (br. s., 1 H), 1,77 (d, J=9.94 Hz, 2 H), 1.61 (d, J=10.47 Hz, 2 H), 1.50 (br. s., 1 H), 1.06 (br. s., 2 H), 0.92 (d, J=8.32 Hz, 2 H). Example 355 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(hydroxymethyl)cyclopentyl)methyl)-2H-tetrazol-5 15 yl)-6-methylpicolinamide 0 - HN OH -O N .:'N - NN A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (325 mg), cis-cyclopentane-1,3-dimethanol 20 (Bioorg. Med. Chem. Lett. 2005, 15, 2685-2688) (203 mg), and polymer supported triphenylphosphine (1.27 g) in anhydrous tetrahydrofuran (15 mL) was cooled in an ice bath. . Di-terd-butyl azodicarboxylate (345 mg) was added and the mixture was placed in an ultrasonic bath for 30 minutes. The mixture was filtered and the resin was washed with tetrahydrofuran. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 25 40/60 - 70/30). The product was dissolved in dichloromethane (20 mL) and stirred with Argonaut MP
CO
3 H resin (2.62 mmol/g, 0.9 g) and eluting through a Stratosphere MP-CO 3 H SPE column. The eluent was concentrated to afford the title compound as an oil (245 mg). MS (ES+) m/z 437 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.2 Hz, 1 H), 6.87 - 6.92 (m, 2 H), 6.79 (dd, J=8.1, 1.5 Hz, 1 H), 4.67 - 4.77 (m, 2 H), 4.49 (d, J=6.6 Hz, 2 30 H), 4.41 (t, J=5.1 Hz, 1 H), 3.71 (s, 3 H), 3.23 - 3.32 (m, 2 H), 2.65 (s, 3 H), 2.50 - 2.59 (m, 1 H), 1.96 2.07 (m, 1 H), 1.74 - 1.84 (m, 1 H), 1.57 - 1.71 (m, 2 H), 1.31 - 1.42 (m, 2 H), 0.96 - 1.06 (m, 1 H). 373 WO 2009/016498 PCT/IB2008/002046 Example 356 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(aminomethyl)cyclopentyl)methy)-2H-tetrazol-5-yI) 6-methylpicolinamide SHN
NH
2 -O N N Nx -- N'N 5 Step 1: Preparation of rac-((1S*,3R*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)cvclopentyl)methyl methanesulfonate 00/ HN O O / O N HN NN -. N'N Methanesulfonyl chloride (0.160 mL) was added to a solution of rac-N-(3-methoxybenzyl)-4 (2-((( 1R*,3S*)-3-(hydroxymethyl)cyclopentyl)methyl)-2H-tetrazol-5-y)-6-methylpicolinamide (prepared 10 as described in Example 355) (742 mg) in pyridine (15 mL) cooled in an ice bath. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20). The combined fractions were made basic with 5% aqueous sodium bicarbonate (3 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over 15 magnesium sulfate, filtered, and concentrated to afford the title compound (752 mg). MS (ES+) m/z 515 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.87 - 6.92 (m, 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.76 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 4.05 - 4.14 (m, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.56 - 2.64 (m, 1 H), 2.52 (s, 3 H), 2.25 - 2.36 (m, 1 H), 1.85 - 1.94 (m, 1 H), 1.67 - 1.77 (m, 2 H), 1.38 - 1.48 (m, 2 H), 1.04 - 1.15 (m, 1 20 H). Step 2: Preparation of rac-N-(3-methoxvbenzvl)-4-(2-(((1R*,3S*)-3-(aminomethyl)cvclopentVl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide N O
NH
2 -O N :N N1x -N N'N Ammonium hydroxide (2 mL) was added to a solution of rac-((1 S*,3R*)-3-((5-(2-((3 25 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)cyclopentyl)methy methanesulfonate (227 mg) in DMSO (2 mL) and the mixture was heated to 70 *C overnight. The mixture was poured into water (10 mL) and extracted with dichloromethane (2 x 5 mL). The combined organic layers were washed with water (5 mL), dried over magnesium sulfate, filtered and 374 WO 2009/016498 PCT/IB2008/002046 concentrated. The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 30/70 - 60/40). The product containing fractions were concentrated. The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (5 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title 5 compound as an oil (110 mg), MS (ES+) m/z 436 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.72 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.50 - 2.59 (m, 1 H), 1.78 - 1.94 (m, 2 H), 1.62 - 1.72 (m, 2 H), 1.23 - 1.44 (m, 2 H), 0.90 - 1.02 (m, 1 H). Example 357 10 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 R*,3S*)-3 (methylsulfonamidomethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl)picolinamide HN ON O O -O N N N - NN Methanesulfonyl chloride (11.4 pL) was added to a mixture of rac-N-(3-methoxybenzyl)-4-(2 (((1R*,3S*)-3-(aminomethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (prepared as 15 described in Example 356) (53 mg) and diisopropylethylamine (30 pL) in anhydrous tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated. The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 75/25). The product containing fractions were concentrated. The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (3 x 10 mL). The combined organic layers 20 were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an oil (63 mg). MS (ES+) m/z 514 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.87 - 6.95 (m, 3 H), 6.80 (d, J=8.1 Hz, 1 H), 4.74 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 3.71 (s, 3 H), 2.87 (t, J=6.6 Hz, 2 H), 2.83 (s, 3 H), 2.65 (s, 3 H), 2.52 - 2.62 (m, 1 H), 2.00 - 2.11 (m, 1 H), 1.82 - 1.92 (m, 1 H), 1.65 - 1.74 (m, 2 H), 1.28 - 1.47 (m, 2 H), 25 0.95 - 1.06 (m, 1 H). Example 358 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide N O H -O - Nz N N NN 375 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of (3S)-tert-butyl 3-((5-(2-((3-methoxvbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)piperidine-1 -carboxylate -O - NzN N NI N-(3-Methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 5 of the synthesis of N-(3-Methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (324 mg, 1.0 mmol), polymer supported triphenylphosphine (698 mg, 1.5 mmol), and (S)-1-Boc-3-(hydroxymethyl)piperidine (258 mg, 1.2 mmol) were suspended in tetrahydrofuran (16 mL). Di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol) was added. The mixture was allowed to stir for 18 hours. The reaction mixture was filtered and the resin washed with 10 tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1; 1/1). Fractions containing the product were concentrated to afford the title compound as an oil (461 mg, 88%). MS (ES+) m/z 522 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) ppm 9.24 (t, J=6.4 Hz, 1 H), 8.41 (d, J=0.8 Hz, 1 H), 8.07 (d, J=1.1 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.87 (m, 2 H), 6.79 (dd, J=8.0, 2.1 Hz, 1 H), 4.77 - 4.66 (m, 2 H), 4.48 (d, 15 J=6.6 Hz, 2 H), 3.70 (s, 3 H), 3.78 - 3.62 (m, 2 H), 2.82 (br. s., 1 H), 2.65 (s, 3 H), 2.12 (br. s., 1 H), 1.75 - 1.56 (m, 2 H), 1.37 - 1.17 (m, 12 H). Step 2: Preparation of N-(3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide N O H -O - NzN N 20 (3S)-tert-Butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)piperidine-1-carboxylate (455 mg, 0.72 mmol) was dissolved in dichloromethane (5.0 mL). Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added and the solution was shaken for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The mixture was washed with 1N NaOH solution (2 x 10 mL). The organic layer was dried 25 over sodium sulfate and concentrated to afford the title compound as an oil (349 mg, 94%). MS (ES+) m/z 422 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.1 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.86 (m, 2 H), 6.79 (dd, J=7.9, 2.1 Hz, 1 H), 4.74 - 4.62 (m, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.70 (s, 3 H), 2.83 - 2.74 (m, 2 H), 2.65 (s, 3 H), 2.47 - 2.40 (m, 1 H), 2.35 (dd, J=12.1, 9.5 Hz, 1 H), 2.18 - 2.07 (m, 1 H), 1.68 - 1.52 (m, 2 H), 1.40 - 1.27 (m, 1 H), 30 1.16 (qd, J=11.1, 3.2 Hz, 1 H). 376 WO 2009/016498 PCT/IB2008/002046 Example 359 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)-1 -(methylsulfonyl)piperidin-3-yl)methyl)-2H-tetrazol-5 yl)picolinamide O HN OSO -O - NzN N N 5 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 358) (165 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (98 pL, 0.71 mmol) and methanesulfonyl chloride (41 pL, 0.53 mmol) were added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). 10 The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (heptane/EtOAc, 1/1; 1/2; 1/4) to afford the title compound as a foaming solid (116 mg, 66%). MS (ES+) m/z 500 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 - 9.20 (m, 1 H), 8.43 (s, 1 H), 8.07 (s, 1 H), 7.24 (t, J=7.9 Hz, 1 H), 6.94 - 6.89 (m, 2 H), 6.81 (d, J=7.7 Hz, 1 H), 4.86 - 4.73 (m, 2 H), 4.51 (d, J=5.9 Hz, 2 H), 3.73 (s, 3 H), 3.48 - 3.36 (m, 2 H), 2.84 (s, 3 H), 2.83 15 2.75 (m, 1 H), 2.72 (t, J=9.9 Hz, 1 H), 2.67 (s, 3 H), 2.35 (br. s., 1 H), 1.80 - 1.68 (m, 2 H), 1.57 - 1.46 (m, 1 H), 1.29 - 1.18 (m, 1 H). Example 360 N-(3-Methoxybenzyl)-4-(2-(((S)-1 -acetylpiperidin-3-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide HN -0 - N N I 20 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 358) (165 mg, 0.35 mmol) was dissolved in dichloromethane (5.0 mL). Triethylamine (98 pL, 0.71 mmol), 4-(dimethylamino)pyridine (8.6 mg, 0.07 mmol), and acetyl chloride (30 pL, 0.42 mmol) was added. The mixture was allowed to stir at room temperature for 20 25 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq. sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (CH 2
CI
2 /methanol, 100/1; 100/2) to afford the title compound as an oil (160 mg, 100%). MS (ES+) m/z 464 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.40 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.21 30 (t, J=8.1 Hz, 1 H), 6.91 - 6.86 (m, 2 H), 6.79 (dd, J=8.2, 2.1 Hz, 1 H), 4.85 - 4.66 (m, 2 H), 4.48 (d, J=6.4 Hz, 2 H), 4.12 (dd, J=12.6, 3.4 Hz, 0.5 H), 4.01 (d, J=13.0 Hz, 0.5 H), 3.70 (s, 3 H), 3.64 (d, J=13.2 Hz, 0.5 H), 3.52 - 3.43 (m, 0.5 H), 3.00 (dd, J=13.4, 10.3 Hz, 1 H), 2.75 - 2.68 (m, 0.5 H), 2.65 377 WO 2009/016498 PCT/IB2008/002046 (s, 3 H), 2.59 (dd, J=12.7, 10.3 Hz, 0.5 H), 2.26 - 2.18 (m, 0.5 H), 2.13 - 2.06 (m, 0.5 H), 1.95 (s, 1.5 H), 1.93 (s, 1.5 H), 1.74 - 1.53 (m, 2 H), 1.44 - 1.19 (m, 2 H). Example 361 N-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide HN O H -O - N N N N 5 Step 1: Preparation of (3R)-tert-butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)piperidine-1 -carboxylate
-
H0 HN O O -o - NN N N\ N-(3-Methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 10 5 of the synthesis of N-(3-Methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (324 mg, 1.0 mmol), polymer supported triphenylphosphine (698 mg, 1.5 mmol), and (R)-1-Boc-3-(hydroxymethyl)piperidine (258 mg, 1.2 mmol) were suspended in tetrahydrofuran (16 mL). Di-ter-butyl azodicarboxylate (345 mg, 1.5 mmol) was added. The mixture was allowed to stir for 18 hours. The reaction mixture was filtered and the resin washed with 15 tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1; 1/1). Fractions containing product were concentrated and repurified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1) to afford the title compound as a foaming solid (352 mg, 67%). MS (ES+) m/z 522 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.41 (d, J=0.8 Hz, 1 H), 8.07 (d, J=1.2 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 20 6.87 (m, 2 H), 6.79 (dd, J=8.1, 1.8 Hz, 1 H), 4.78 - 4.66 (m, 2 H), 4.48 (d, J=6.4 Hz, 2 H), 3.70 (s, 3 H), 3.66 (br. s., 2 H), 2.82 (br. s., 1 H), 2.65 (s, 3 H), 2.13 (br. s., 1 H), 1.74 - 1.67 (m, 1 H), 1,64 - 1.57 (m, 1 H), 1.35 - 1.21 (m, 12 H). 378 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(3-methoxvbenzyl)-6-methyl-4-(2-((R)-piperidin-3-vlmethyl)-2H-tetrazol-5 yl)picolinamide N O H -O - N N N N (3R)-tert-Butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 5 yl)methyl)piperidine-1-carboxylate (348 mg, 0.65 mmol) was dissolved in dichloromethane (5.0 mL). Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added and the solution was shaken for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The mixture was washed with 1N NaOH solution (2 x 10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (283 mg, 96%). MS (ES+) 10 m/z 422 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.2 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.90 - 6.86 (m, 2 H), 6.79 (dd, J=7.9, 2.1 Hz, 1 H), 4.74 - 4.62 (m, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.70 (s, 3 H), 2.81 - 2.74 (m, 2 H), 2.65 (s, 3 H), 2.46 - 2.39 (m, 1 H), 2.34 (dd, J=11.9, 9.5 Hz, 1 H), 2.15 - 2.07 (m, 1 H), 1.66 - 1.52 (m, 2 H), 1.38 - 1.26 (m, 1 H), 1.16 (qd, J=10.5, 3.8 Hz, 1 H). 15 Example 362 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)piperidin-3-yl)methyl)-2H-tetrazol-5 yl)picolinamide 0 HN 0 SZZO -O - NzN N N N-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide 20 (prepared as described in Example 361) (135 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (83 pL, 0.60 mmol) and methanesulfonyl chloride (35 pL, 0.48 mmol) were added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by 25 silica column chromatography (heptane/EtOAc, 1/1; 1/2; 1/4) to afford the title compound as a foaming solid (99 mg, 66%). MS (ES+) m/z 500 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.95 - 6.89 (m, 2 H), 6.82 (d, J=8.1 Hz, 1 H), 4.87 - 4.74 (m, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.73 (s, 3 H), 3.48 - 3.36 (m, 2 H), 2.85 (s, 3 H), 2.79 (t, J=10.4 Hz, 1 H), 2.72 (t, J=10.2 Hz, 1 H), 2.67 (s, 3 H), 2.36 (br. s., 1 H), 1.80 - 1.68 (m, 2 H), 1.58 30 1.47 (m, 1 H), 1.29 - 1.19 (m, 1 H). 379 WO 2009/016498 PCT/IB2008/002046 Example 363 N-(3-Methoxybenzyl)-4-(2-(((R)-1 -acetylpiperidin-3-yl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide P-HN O 0 -O - NN N N 5 N-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 361) (135 mg, 0.30 mmol) was dissolved in dichloromethane (5.0 mL). Triethylamine (83 pL, 0.60 mmol), 4-(dimethylamino)pyridine (7.3 mg, 0.06 mmol), and acetyl chloride (25 pL, 0.36 mmol) was added. The mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq. 10 sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2). Fractions were concentrated to afford the title compound as an oil (123 mg, 88%). MS (ES+) m/z 464 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.44 (s, 1 H), 8.09 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.95 - 6.89 (m, 2 H), 6.82 (d, J=8.1 Hz, 1 H), 4.88 - 4.68 (m, 2 H), 4.51 15 (d, J=6.2 Hz, 2 H), 4.17 - 4.12 (m, 0.5 H), 4.06 - 4.00 (m, 0.5 H), 3.79 - 3.73 (m, 0.5 H), 3.73 (s, 3 H), 3.71 - 3.64 (m, 0.5 H), 3.08 - 3.00 (m, 1 H), 2.80 - 2.72 (m, 0.5 H), 2.68 (s, 3 H), 2.65 - 2.60 (m, 0.5 H), 2.29 - 2.23 (m, 0.5 H), 2.17 - 2.10 (m, 0.5 H), 1.98 (s, 1.5 H), 1.96 (s, 1.5 H), 1.77 - 1.59 (m, 2 H), 1.46 - 1.25 (m, 2 H). Example 364 20 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazo-5 yl)picolinamide F 0 O -P HN- H -O - N N N N '\ 380 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of (3S)-tert-butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)methyl)piperidine-1 -carboxylate F 0 O -Q HN -0" -O -- NN N N N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as 5 described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (342 mg, 1.0 mmol), polymer supported triphenylphosphine (698 mg, 1.5 mmol), and (S)-1-Boc-3-(hydroxymethyl)piperidine (258 mg, 1.2 mmol) were suspended in tetrahydrofuran (16 mL). Di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol) was added. The mixture was allowed to stir for 18 hours. The reaction mixture was 10 filtered and the resin washed with tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by column chromatography (heptane/EtOAc, 2/1; 1/1). Fractions containing the product were concentrated to afford the title compound as an oil (455 mg, 84%). MS (ES+) m/z 540 (M+H). 'H NMR (400 MHz, DMSO-d) J ppm 9.26 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.07 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.7, 8.3 Hz, 1 H), 6.87 (ddd, J=8.3, 4.4, 1.9 15 Hz, 1 H), 4.77 - 4.66 (m, 2 H), 4.47 (d, J=5.9 Hz, 2 H), 3.79 (s, 3 H), 3.72 - 3.62 (m, 2 H), 2.85 - 2.79 (m, 1 H), 2.65 (s, 3 H), 2.17 - 2.09 (m, 1 H), 1.76 - 1.50 (m, 2 H), 1.36 - 1.21 (m, 12 H). Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H tetrazol-5-yl)picolinamide F 0 -P HN H -O - NaN N N\ 20 (3S)-tert-Butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)piperidine-1-carboxylate (450 mg, 0.63 mmol) was dissolved in dichloromethane (5.0 mL). Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added and the solution was shaken for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The mixture was washed with IN NaOH solution (2 x 10 mL). The organic 25 layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (331 mg, 97%). MS (ES+) m/z 440 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.39 (d, J=0.9 Hz, 1 H), 8.05 (d, J=1.2 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.6, 8.4 Hz, 1 H), 6.87 (ddd, J=8.2, 4.4, 1.9 Hz, 1 H), 4.73 - 4.62 (m, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 2.81 2.74 (m, 2 H), 2.65 (s, 3 H), 2.46 - 2.39 (m, 1 H), 2.34 (dd, J=12.0, 9.5 Hz, 1 H), 2.15 - 2.07 (m, 1 H), 30 1.67 - 1.52 (m, 2 H), 1.38 - 1.26 (m, 1 H), 1.16 (qd, J=10.7, 3.5 Hz, 1 H). 381 WO 2009/016498 PCT/IB2008/002046 Example 365 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((R)-1 -(methylsulfonyl)piperidin-3-yl)methyl)-2H tetrazol-5-yl)picolinamide F O - HN OTO -O - Nz N N N/\ I NN 5 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide (prepared as described in Example 364) (160 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (95 pL, 0.68 mmol) and methanesulfonyl chloride (40 pL, 0.51 mmol) were added, The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 10 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (heptane/EtOAc, 1/1; 1/2; 1/4) to afford the title compound as a foaming solid (111 mg, 63%). MS (ES+) m/z 518 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.44 (s, 1 H), 8.09 (s, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 7.14 (dd, J=11.5, 8.2 Hz, 1 H), 6.91 (d, J=2.2 Hz, 1 H), 4.88 - 4.75 (m, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.82 (s, 3 H), 3.49 - 3.37 (m, 15 2 H), 2.85 (s, 3 H), 2.83 - 2.77 (m, 1 H), 2.72 (t, J=9.9 Hz, 1 H), 2.68 (s, 3 H), 2.42 - 2.31 (m, 1 H), 1.80 - 1.69 (m, 2 H), 1.59 - 1.47 (m, 1 H), 1.30 - 1.19 (m, 1 H). Example 366 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)-1-acetylpiperidin-3-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F N O -O - NzN N N x N N 20 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide (prepared as described in Example 364) (160 mg, 0.34 mmol) was dissolved in dichloromethane (5.0 mL). Triethylamine (95 pL, 0.68 mmol), 4-(dimethylamino)pyridine (8.4 mg, 0.07 mmol), and acetyl chloride (29 pL, 0.41 mmol) was added. The mixture was allowed to stir at room 25 temperature for 20 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq. sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2). Fractions were concentrated to afford the title compound as a foaming solid (123 mg, 77%). MS (ES+) m/z 482 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (t, 30 J=6.4 Hz, I H), 8.40 (s, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.6, 8.4 Hz, 1 H), 6.87 (ddd, J=8.2, 4.3, 1.9 Hz, 1 H), 4.85 - 4.66 (m, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 4.11 (dd, J=12.6, 3.5 Hz, 0.5 H), 4.01 (d, J=13.4 Hz, 0.5 H), 3.79 (s, 3 H), 3.73 (d, J=14.0 Hz, 0.5 H), 3.64 (d, 382 WO 2009/016498 PCT/IB2008/002046 J=12.8 Hz, 0.5 H), 3.00 (dd, J=13.2, 10.1 Hz, 1 H), 2.76 - 2.67 (m, 0.5 H), 2.65 (s, 3 H), 2.59 (dd, J=12,7, 10.4 Hz, 0.5 H), 2.26 - 2.19 (m, 0.5 H), 2.13 - 2.05 (m, 0.5 H), 1.95 (s, 1.5 H), 1.93 (s, 1.5 H), 1.75 - 1.54 (m, 2 H), 1.46 - 1.19 (m, 2 H). Example 367 5 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide F 0 - HNH -O - NN N N\ Step 1: Preparation of (3R)-terd-butyl 3-((5-(2-((4-fluoro-3-methoxvbenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)methvl)piperidine-1-carboxylate F N 0 0 0 NN 10 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (342 mg, 1.0 mmol), polymer supported triphenylphosphine (698 mg, 1.5 mmol), and (R)-1-Boc-3 15 (hydroxymethyl)piperidine (258 mg, 1.2 mmol) were suspended in tetrahydrofuran (16 mL). Di-ter butyl azodicarboxylate (345 mg, 1.5 mmol) was added. The mixture was allowed to stir for 18 hours, The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1; 1/1). Fractions containing the product were concentrated to afford the title compound as a foaming 20 solid (472 mg, 87%). MS (ES+) m/z 540 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.07 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=1 1.5, 8.3 Hz, 1 H), 6.87 (ddd, J=8.3, 4.4, 1.9 Hz, 1 H), 4.77 - 4.66 (m, 2 H), 4.47 (d, J=6.0 Hz, 2 H), 3.79 (s, 3 H), 3.70 - 3.62 (m, 2 H), 2.81 (br. s., 1 H), 2.65 (s, 3 H), 2.12 (br. s., 1 H), 1.74 - 1.56 (m, 2 H), 1.27 (br. s., 12 H). 383 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-methoxybenzvl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H tetrazol-5-yl)picolinamide F 0 -P HN H -O - N-N N N x (3R)-tert-Butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H 5 tetrazol-2-yl)methyl)piperidine-1 -carboxylate (465 mg, 0.67 mmol) was dissolved in dichloromethane (5.0 mL), Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added and the solution was shaken for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The mixture was washed with 1N NaOH solution (2 x 10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (362 mg, 10 96%). MS (ES+) m/z 440 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.26 (t, J=6.4 Hz, 1 H), 8.40 (d, J=0.8 Hz, 1 H), 8.05 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.7, 8.3 Hz, 1 H), 6.87 (ddd, J=8.2, 4.4, 2.0 Hz, 1 H), 4.73 - 4.62 (m, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 2.80 2.74 (m, 2 H), 2.65 (s, 3 H), 2.46 - 2.39 (m, 1 H), 2.33 (dd, J=11.9, 9.5 Hz, 1 H), 2.10 (br. s., 1 H), 1.66 - 1.51 (m, 2 H), 1.39 - 1.26 (m, 1 H), 1.15 (qd, J=10.6, 3.5 Hz, 1 H). 15 Example 368 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)piperidin-3-yl)methyl)-2H tetrazol-5-yl)picolinamide F 0 -O - NaN N N\ N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5 20 yl)picolinamide (prepared as described in Example 367) (175 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (101 pL, 0.73 mmol) and methanesulfonyl chloride (42 pL, 0.54 mmol) were added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was 25 purified by silica column chromatography (CH 2
CI
2 /methanol, 100/1; 100/2; 100/4). The resulting impure product was further purified by silica column chromatography (heptane/EtOAc, 1/1; 1/2; 1/4) to afford the title compound as a foaming solid (99 mg, 53%). MS (ES+) m/z 518 (M+H). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.2 Hz, 1 H), 8. 44 (s, 1 H), 8.08 (s, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 7.13 (dd, J=11.5, 8.2 Hz, 1 H), 6.94 - 6.88 (m, 1 H), 4.87 - 4.74 (m, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.82 30 (s, 3 H), 3.49 - 3.37 (m, 2 H), 2.85 (s, 3 H), 2.84 - 2.76 (m, 1 H), 2.75 - 2.69 (m, 1 H), 2.68 (s, 3 H), 2.36 (br. s., 1 H), 1.81 - 1.68 (m, 2 H), 1.58 - 1.47 (m, 1 H), 1.30 - 1.18 (m, 1 H). 384 WO 2009/016498 PCT/IB2008/002046 Example 369 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1 -acetylpiperidin-3-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F N- O -P HN r -O - NzN N N 5 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-piperidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide (prepared as described in Example 367) (175 mg, 0.36 mmol) was dissolved in dichloromethane (5.0 mL). Triethylamine (73 pL, 0.73 mmol), 4-(dimethylamino)pyridine (8.9 mg, 0.06 mmol), and acetyl chloride (31 pL, 0.36 mmol) was added. The mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed 10 with saturated aq. sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2) to afford the title compound as a foaming solid (134 mg, 79%). MS (ES+) m/z 482 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 7.13 (dd, J=11.7, 8.4 Hz, 1 H), 6.93 - 6.88 (m, 1 H), 4.88 - 4.69 (m, 2 15 H), 4.50 (d, J=6.2 Hz, 2 H), 4.17 - 4.12 (m, 0.5 H), 4.06 - 4.00 (m, 0.5 H), 3.82 (s, 3 H), 3.79 - 3.73 (m, 0.5 H), 3.70 - 3.64 (m, 0.5 H), 3.04 (t, J=12.8 Hz, 1 H), 2.80 - 2.72 (m, 0.5 H), 2.68 (s, 3 H), 2.67 - 2.60 (m, 0.5 H), 2.30 - 2.22 (m, 0.5 H), 2.18 - 2.09 (m, 0.5 H), 1.98 (s, 1.5 H), 1.96 (s, 1.5 H), 1.77 - 1.59 (m, 2 H), 1.47 - 1.24 (m, 2 H). Example 370 20 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide F 0 -P HN -o - NN NH NH Step 1: Preparation of (3R)-tert-butyl 3-((5-(2-((4-fluoro-3-methoxvbenzvl)carbamovl)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)methyl)pvrrolidine-1-carboxylate F 0 O O HN -0 NN N N\ / NN 25 A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 385 WO 2009/016498 PCT/IB2008/002046 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (0.45 g, 1.3 mmol), (R)-tert-butyl 3-(hydroxymethyl) pyrrolidine-1-carboxylate (0.27 g, 1.3 mmol), and polymer supported triphenylphosphine (0.73 g, 1.6 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 0 *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.45 g, 2.0 mmol) was added. The mixture 5 was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography (0-50%, ethyl acetate/heptane) to afford the title compound. Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolidin-3-ylmethyl)-2H tetrazol-5-yl)picolinamide F N O - HNN -O N ~ NH 10 Trifluoroacetic acid (3 mL) was added to a solution of (3R)-tert-butyl 3-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2-yl)methyl)pyrrolidine-1-carboxylate in dichloromethane (5 mL). After 30 min at ambient temperature, the reaction mixture was neutralized to pH 7 with 2.5 N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3 x 10 mL). 15 The combined organic layers were washed with water (2 x 10 mL) followed by brine (10 mL), dried over sodium sulfate, and concentrated to afford the title compound (0.35g, 63%). LC/MS (5-100%
CH
3
CN/H
2 0, 5 min) 2.05 min, m/z 426 (M+H). Example 371 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)pyrrolidin-3-yl)methyl)-2H 20 tetrazol-5-yl)picolinamide F 0 HN O'/ -O - NN' N Triethylamine (0.037 mL) and methane sulfonyl chloride (0.028 mg, 0.21 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolidin-3-ylmethyl)-2H-tetrazol-5 yl)picolinamide (prepared as described in Example 370) (0.075 g, 0.18 mmol) in dichloromethane (3 25 mL). The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified via reverse phase preparative HPLC to afford the title compound as an oil (15 mg, 17%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (br. s., 1 H), 8.44 (s, 1 H), 8.08 (s, 1 H), 7.10 - 7.21 (m, 2 H), 6.91 (br. s., 1 H), 4.90 (d, J=7.0 Hz, 2 H), 4.51 (d, J=5.9 Hz, 2 H), 3.82 (s, 3 H), 3.46 (br. s., 1 H), 3.07 - 3.17 (m, 1 H), 2.91 (s, 5 H), 2.68 (s, 4 H), 2.05 (br. s., 1 30 H), 1.81 (d, J=7.7 Hz, 1 H). 386 WO 2009/016498 PCT/IB2008/002046 Example 372 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1 -acetylpyrrolidin-3-yi)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide F- - HN 00 F0 NN -O - NaN N NN 5 Triethylamine (0.037 mL) and acetyl chloride (0.017 mg, 0.21 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolidin-3-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 370) (0.075 g, 0.18 mmol) in dichloromethane (3 mL). The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified via reverse phase preparative HPLC to afford the title compound as an oil (15 10 mg, 18%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (br. s., 1 H), 8.44 (s, 1 H), 8.08 (s, 1 H), 7.14 (d, J=2.9 Hz, 1 H), 7.10 - 7.21 (m, 1 H), 6.91 (br. s., 1 H), 4.88 (t, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.82 (s, 3 H), 3.42 - 3.51 (m, 3 H), 3.12 - 3.18 (m, 1 H), 2.83 - 2.99 (m, 1 H), 2.68 (s, 3 H), 1.97 - 2.13 (m, 1 H), 1.92 (br. s., 3 H), 1.64 - 1.86 (m, 1 H). Example 373 15 2-((R)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)pyrrolidin-1-yl)-2-oxoethyl acetate F N 0 O 0 N 0 -o - NN N Triethylamine (0.037 mL) and acetoxy acetyl chloride (0.029 mg, 0.21 mmol) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolidin-3-ylmethyl)-2H-tetrazol-5 20 yl)picolinamide (prepared as described in Example 370) (0.075 g, 0.18 mmol) in dichloromethane (3 mL). The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC to afford the title compound. Example 374 25 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1 -(2-hydroxyacetyl)pyrrolidin-3-yl)methyl)-2H-tetrazol 5-yl)-6-methylpicolinamide 387 WO 2009/016498 PCT/IB2008/002046 F N OH -0 - NN N sN-N f A mixture of 2-((R)-3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl acetate (prepared as described in Example 373) and 2.5 N aqueous sodium hydroxide (1 mL) in acetonitrile (3 mL) was stirred for 2 hours at room temperature. 5 The acetonitrile was removed in vacuo and the aqueous residue was acidified to pH 5 with 10% aqueous hydrochloric acid. The resulting solid was filtered and dried to afford .9 mg (10%) of the title compound as a white solid. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (br. s., 1 H), 8.44 (s, 1 H), 8.08 (s, 1 H), 7.17 (br. s., I H), 7.11 (s, 1 H), 6.91 (br. s., 1 H), 4.89 (d, J=6.2 Hz, 2 H), 4.51 (d, J=6.2 Hz, 3 H), 3.97 (br. s., 2 H), 3.82 (s, 3 H), 3.57 (br. s., 2 H), 3.37 (br. s., 2 H), 2.82 - 3.07 (m, 1 H), 2.68 (s, 3 10 H), 1.98 - 2.12 (m, 1 H). Example 375 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-((1 -benzyl-5-oxopyrrolidin-3-yl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide F N N 15 A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (0.17 g, 0.48 mmol), 1 benzyl-4-(hydroxymethyl)pyrrolidin-2-one (0.99 g, 0.48 mmol) (Org. Lett. 1999, 1, 799-801), and polymer supported-triphenylphosphine (0.32 g, 0.72 mmol) in anhydrous tetrahydrofuran (10 mL) was 20 cooled to 0*C in an ice bath for 15 minutes. Di-tert-butyl azodicarboxylate (0.13 g, 0.58 mmol) was added and the reaction was allowed to warm to room temperature over 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to afford the title compound as a beige oil (0.18 g, 71%). 'H NMR (400 MHz, DMSO-ds) J ppm 9.19 - 9.29 (m, I H), 8.41 (s, I H), 8.04 (s, I H), 7.32 (t, J=7.69 25 Hz, 2 H), 7.20 (d, J=6.95 Hz, 2 H), 7.17 - 7.27 (m, 1 H), 7.14 (dd, J=11.71, 8.42 Hz, 1 H), 6.91 (d, J=6.22 Hz, 1 H), 4.89 (d, J=6.95 Hz, 2 H), 4.51 (d, J=6.22 Hz, 2 H), 4.35 (s, 2 H), 3.82 (s, 3 H), 3.40 (t, J=8.97 Hz, 1 H), 3.13 - 3.19 (m, 1 H), 2.67 (s, 3 H), 2.57 (d, J=7.69 Hz, 1 H), 2.35 (dd, J=16.65, 6.77 Hz, 1 H), 1.37 (d, J=15.37 Hz, 1 H), 1.24 (dd, J=12.63, 5.67 Hz, 1 H). 388 WO 2009/016498 PCT/IB2008/002046 Example 376 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H tetrazol-5-yl)picolinamide 0 HO \ HN -0 N-N 0 N IN - N' 0 5 Step 1: Preparation of methyl 6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinate trifluoroacetate 0 0 N NH - NN Methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 10 methylpicolinamide, Example 153) (1.99 g, 9.08mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1 carboxylate (1.95 g, 9.08 mmol) were suspended in anhydrous tetrahydrofuran (50 mL) along with polymer supported-triphenylphosphine (6.05 g, 13.6 mmol). The mixture was cooled to O *C in an ice bath for 15 minutes and then di-tert-butyl azodicarboxylate (2.51 g, 10.9 mmol) was added. The mixture was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture 15 was filtered and the filtrate was concentrated. The residue was purified on silica (70 g, 0-50 % ethyl acetate/heptane). The resulting intermediate was dissolved in dichloromethane (15 mL) and stirred with trifluoroacetic acid (5.0 mL) for 1 hour at room temperature. The reaction mixture was concentrate to 1/3 volume and tert-butyl methyl ether (5 mL) was slowly added to cause precipitation. The resulting solids were collected by filtration, washed with diethyl ether (3 x 5 mL) and dried to 20 afford the title compound as a beige solid (3.3 g, 84%). MS (ES+) m/z 317 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 8.72 (br. s., 1 H), 8.37 (s, 1 H), 8.09 (s, 1 H), 4.78 (d, J=6.7 Hz, 2 H), 3.90 (s, 3 H), 3.27 (d, J=12.4 Hz, 2 H), 2.87 (d, J=10.8 Hz, 2 H), 2.63 (s, 3 H), 2.22 - 2.41 (m, 1 H), 1.66 - 1.82 (m, 2 H), 1.30 - 1.57 (m, 2 H). Step 2: Preparation of methyl 6-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 25 yl)picolinate 0 0 N N NI !r N N " -~ N' 0 Triethylamine (0.34 mL, 2.4 mmol) was added to a solution of methyl 6-methyl-4-(2-(piperidin 4-ylmethyl)-2H-tetrazol-5-yl)picolinate trifluoroacetate (0.50 g, 1.2 mmol) in 2-methyltetrahydrofuran (5 mL). A solution of methane sulfonyl chloride (0.16 mL) in 2-methyltetrahydrofuran (2 mL) was added 389 WO 2009/016498 PCT/IB2008/002046 and the mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-50 % ethyl acetate/heptane) to afford the title compound (0.46 g, 100%). MS (ES+) m/z 395 (M+H). Step 3: Preparation of 6-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-vI)methyl)-2H-tetrazol-5-vl)picolinic 5 acid 0 HO N- N -- N N I / - NN S-_ I1 0 An aqueous sodium hydroxide solution (2.5 N, 2.5 mL) was added to a solution of methyl 6 methyl-4-(2-((I-(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)picolinate (0.46g, 1.2 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 3 hours. The tetrahydrofuran 10 was removed in vacuo and the aqueous residue was acidified with concentrated hydrochloric acid to pH 6, The resulting precipitate was filtered, washed with water (3 x 10 mL), and then dried to afford the title compound (0.41 g, 93%). MS (ES+) m/z 381 (M+H). Step 4: Preparation of N(3-(2-hydroxyethoxy)benzvl)-6-methyl-4-(2-((1-(methylsulfonvy)piperidin-4 yI)methyl)-2H-tetrazol-5-vl)picolinamide 0 HO HN -0 /\ N-~N 0 H \ P NN H I 'CN // O-r N N . --- N'N 15 0 1-Hydroxybenzatriazole (22 mg, 0.16 mmol) was added to a solution of 6-methyl-4-(2-((1 (methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)picolinic acid ( 0.050 g, 0.13 mmol) in 2-methyl tetrahydrofuran (5 mL). After 15 minutes, 2-(3-(aminomethyl)phenoxy) ethanol (27 mg, 0.16 mmol) and polymer supported carbodiimide (0.16 g, 0.20 mmol) were added. The mixture was stirred for 18 20 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified via reverse phase preparative HPLC to afford the title compound (25 mg, 36%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.20 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.20 (t, J=8.1 Hz, 1 H), 6.85 - 6.96 (m, 2 H), 6.79 (d, J=7.3 Hz, 1 H), 4.76 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.93 (t, J=5.1 Hz, 2 H), 3.67 (q, J=5.1 Hz, 2 H), 3.55 (d, J=1 1.7 Hz, 2 H), 2.81 (s, 3 H), 2.59 - 2.77 (m, 25 5 H), 2.07 - 2.27 (m, 1 H), 1.67 (d, J=12.4 Hz, 2 H), 1.25 - 1.46 (m, 2 H). Example 377 N-(3-Ethoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide 390 WO 2009/016498 PCT/IB2008/002046 SHN 0 /\ N-N 0 / NN 0 The title compound was prepared in a similar manner to N-(3-(2-hydroxyethoxy)benzyl)-6 methyl-4-(2-((1-(methysulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 376, step 4) by reaction with (3-ethoxyphenyl)methanamine (prepared as described in step 2 of the synthesis of 5 N-(3-ethoxybenzyl)-6-methyl-4-(2-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5 yl)picolinamide, Example 180) to afford 28 mg (42%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, I H), 7.20 (t, J=8.1 Hz, 1 H), 6.88 (d, J=5.9 Hz, 2 H), 6.78 (d, J=8.8 Hz, 1 H), 4.76 (d, J=7.3 Hz, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 3.97 (q, J=6.8 Hz, 2 H), 3.55 (d, J=11.7 Hz, 2 H), 2.81 (s, 3 H), 2.58 - 2.77 (m, 5 H), 2.10 - 2.28 (m, 1 H), 1.67 (d, J=11.7 Hz, 2 H), 1.31 10 - 1.44 (m, 2 H), 1.28 (t, J=7.0 Hz, 3 H). Example 378 N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H tetrazol-5-yl)picolinamide F N-\ 0 N HN ~- N' 0 15 The title compound was prepared in a similar manner to N-(3-(2-hydroxyethoxy)benzyl)-6 methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 376, step 4) by reaction with (4-fluoro-3-methylphenyl)methanamine to afford 25 mg (39%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.23 (d, J=6.6 Hz, 1 H), 7.12 7.20 (m, 1 H), 6.99 - 7.10 (m, I H), 4.76 (d, J=6.6 Hz, 2 H), 4.46 (d, J=6.6 Hz, 2 H), 3.55 (d, J=11.7 20 Hz, 2 H), 2.81 (s, 3 H), 2.59 - 2.75 (m, 5 H), 2.07 - 2.27 (m, 4 H), 1.67 (d, J=13.2 Hz, 2 H), 1.26 - 1.45 (m, 2 H). Example 379 N-(3-M eth oxybenzyl) -6-m ethyl -4 -(2 -(piperid in -4-ylmethyl)-2 H-tetrazol-5-yl) pico li nam ide HN /\ N-~N N INH - N 391 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of tert-butyl 4-((5-(2-((3-methoxybenzvl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2- yl)methyl)piperidine-1 -carboxylate - HN -O N N 0 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as 5 described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (1.00 g, 3.10 mmol), tert-butyl 4-(hydroxymethyl) piperidine-1-carboxylate (0.81 g, 3.8 mmol), and polymer supported-triphenylphosphine (2.90 g, 6.21 mmol) were suspended in anhydrous tetrahydrofuran (32 mL). The mixture was cooled to 0 *C in an ice bath for 15 minutes and then di-tert-butyl azodicarboxylate (1.11 g, 4.82 mmol) was added. The 10 mixture was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (20 g, 0-50% gradient ethyl acetate/heptane) to afford the title compound as a white solid (1.52 g, 94%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 6.24 min, m/z 544 (M+Na). Step 2: Preparation of N-(3-methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5 15 yl)picolinamide -NHN -ON NH -N' Trifluoroacetic acid (6 mL) was added to a solution of tert-butyl 4-((5-(2-((3-methoxybenzyl) carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)piperidine- 1 -carboxylate (1.51 g, 2.89 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 1 hour at room temperature and was 20 then concentrated. The residue was purified by reverse phase preparative HPLC to afford the title compound as the trifluoroacetate salt (0.83 g, 56%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.33 min, m/z 422 (M+H). Example 380 N-(3-Methoxybenzyl)-4-(2-((1 -(2 -hydroxy-2-methylpropanoyl)piperidin-4-yl)methyl)-2H-tetrazol 25 5-yl)-6-methylpicolinamide 392 WO 2009/016498 PCT/IB2008/002046 - N O -O N N OH - N' 0 Triethylamine (31 mg, 0.31 mmol) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.023 g, 0.14 mmol) were added to a solution of N-(3-methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H tetrazol-5-yl)picolinamide (prepared as described in Example 379) (75 mg, 0.14 mmol) in N,N 5 dimethylacetamide (2 mL), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x-5 mL). The organic layer was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (10 g, 0-50% ethyl acetate/heptane). The intermediate was dissolved in a mixture of methanol/water (4 mL, 3/1)and 10 potassium carbonate (41 mg, 0.30 mmol) was added. The mixture was stirred for 10 hours at 60*C. The methanol was removed in vacuo and the aqueous residue was acidified with a 10% aqueous solution of hydrochloric acid. This mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue that was purified by reverse phase preparative HPLC to afford 15 the title compound (21 mg, 30%). MS (ES+) m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 5.26 (s, 1 H), 4.71 (d, J=7.3 Hz, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 2.30 (d, J=2.9 Hz, 1 H), 1.58 (d, J=13.2 Hz, 4 H), 1.22 - 1.33 (m, 6 H), 1.19 (br. s., 4 H). Example 381 20 N-(3-Methoxybenzyl)-4-(2-((1-(3-aminopropanoyl)piperidin-4-yl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide - N O -O N /NNH2 - NN I 0 1 -Hydroxybenzotriazole (3.2 mg, 0.024 mmol) was added to a solution of 3-(tert butoxycarbonyl)propanoic acid (27.2 mg, 0.144 mmol) in N,N-dimethylformamide (2 mL). 25 Carbodiimide resin (138 mg, 0.18 mmol, 1.30 mmol/g loading), N-(3-methoxybenzyl)-6-methyl-4-(2 (piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 379) (50.6 mg, 0.120 mmol), and N-methylmorpholine (0.066 mL, 0.60 mmol) were added with dichloromethane (2 mL), and the mixture was agitated overnight at room temperature. The reaction mixture was filtered and the resin was washed with N,N-dimethylformamide followed by dichloromethane. The filtrate was 30 concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min.). The intermediate was added to a 1:1 mixture of trifluoroacetic acid and dichloromethane and 393 WO 2009/016498 PCT/IB2008/002046 stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in dichloromethane, neutralized with MP-carbonate resin, and concentrated to afford the title compound (10 mg, 17%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.572 min., m/z 493 (M+H). 5 Example 382 N-(3-Methoxybenzyl)-4-(2-((1-(2-aminoacetyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide HNO -0 N0 N NN -OI NN
NH
2 O 0 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-((1-(3 10 aminopropanoyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 381) by reaction with 2-(tert-butoxycarbonyl)acetic acid to afford 10 mg (17%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.543 min., m/z 479 (M+H). Example 383 N-(3-Methoxybenzyl)-4-(2-((I -acetylpiperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide SHN -O N-N -- NN 15 0 Acetic anhydride (0.034 mL, 0.356 mmol) and 4-(dimethylamino)pyridine Si bound (862.0 mg, 0.595 mmol, 0.69 mmol/g loading) were added to a solution of N-(3-methoxybenzyl)-6-methyl-4-(2 (piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 379) (50.2 mg, 0.119 mmol) in dichloromethane (2 mL), and the mixture was agitated overnight at room temperature. 20 The reaction mixture was filtered and the resin was washed with N,N-dimethylformamide. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min.) to afford the title compound as a solid (24.5 mg, 44%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 2.959 min., m/z 464 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 0.98 - 1.35 (m, 4 H), 1.57 (m, 2 H), 1.94 (s, 3 H), 2.16 - 2.37 (m, 1 H), 2.44 - 2.57 25 (m, 2 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.71 (d, J=7.3 Hz, 2 H), 6.80 (m, 1 H), 6.86 - 6.95 (m, 2 H), 7.14 - 7.28 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.11 - 9.27 (m, 1 H). Example 384 N-(3-Methoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide 394 WO 2009/016498 PCT/IB2008/002046 SHN -/ NN -o~ ~ N /N N N' 0 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-((1-acetyl piperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide (Example 383) by reaction with methane sulfonylchloride to afford 32.5 mg (55%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 5 min.): 3.154 min., m/z 500 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) J ppm 1.24 - 1.48 (m, 4 H), 1.61 1.72 (m, 2 H), 2.07 - 2.27 (m, 1 H), 2.65 (s, 3 H), 2.81 (s, 3 H), 3.47 - 3.60 (m, 2 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.76 (d, J=7.3 Hz, 2 H), 6.73 - 6.83 (m, 1 H), 6.86 - 6.95 (m, 2 H), 7.15 - 7.27 (m, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.19 (s, 1 H). Example 385 10 N-(3-Methoxybenzyl)-4-(2-((1 -isobutyrylpiperidin-4-yl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide - N O N NNN NO 0 The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-4-(2-((1-acetyl piperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6-m ethylpicolinamide (Example 383) by reaction with isobutyryl 15 chloride to afford 37.2 mg (63%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.296 min., m/z 492 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.00 - 1.37 (m, 6 H), 1.47 - 1.72 (m, 2 H), 2.28 (s, 1 H), 2.65 (s, 3 H), 2.74 - 2.90 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.72 (d, J=7.3 Hz, 2 H), 6.80 (s, 1 H), 6.86 - 6.97 (m, 2 H), 7.22 (s, 1 H), 8.05 (s, 1 H), 8.41 (s, 1 H), 9.19 (s, 1 H). 20 Example 386 N-(3-Methoxybenzyl)-6-methyl-4-(2-((1 -(methylcarbamoyl)piperidin-4-yl)methyl)-2H-tetrazol-5 yl)picolinamide HN N N N, - N' 0 Methylisocyanate (4M solution in dichloromethane, 1 mL) and 4-(dimethylamino)pyridine Si bound 25 (862.0 mg, 0.595 mmol, 0.69 mmol/g loading) were added to a solution of N-(3-methoxybenzyl)-6 methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-y)picolinamide (prepared as described in Example 395 WO 2009/016498 PCT/IB2008/002046 379) in dichloromethane (1 mL), and the mixture was agitated overnight at room temperature. The reaction mixture was filtered and the resin was washed with N,N-dimethylformamide. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH 3
CN/H
2 0, 8 min.) to afford the title compound (35.5 mg, 62%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% 5 CH 3 CN, 1.5 min.): 2.887 min., m/z 479 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.01 - 1.24 (m, 4 H), 1.44 - 1.55 (m, 2 H), 2.20 (s, 1 H), 2.50 - 2.54 (m, 3 H), 2.56 - 2.63 (m, 2 H), 2.65 (s, 3 H), 3.71 (s, 3 H), 4.49 (d, J=6.6 Hz, 2 H), 4.70 (d, J=6.6 Hz, 2 H), 6.30 (s, 1 H), 6.80 (m, 1 H), 6.85 - 6.95 (m, 2 H), 7.22 (s, Hz, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.09 - 9.26 (m, 1 H). Example 387 10 N-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-y)picolinamide F N 0 CI N NH --- N'N Step 1: Preparation of4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-vl)-6 methylpicolinic acid 0 HO N N N I 0 15 A flask was charged with methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (1.0 g, 4.6 mmol), terf-butyl 4-(hydroxymethyl) piperidine-1-carboxylate (2.0 g, 9.1 mmol), polymer supported triphenylphosphine resin (4.2 g, 9.1 mmol, 2.15 mmol/g loading) and tetrahydrofuran (60 mL). The mixture was cooled in an ice bath and 20 di-tert-butylazodicarbxylate (2.1 g, 9.1 mmol) was added. The mixture was stirred for 30 minutes and then allowed to warm to room temperature over 18 hours. The reaction mixture was filtered and the resin was washed with methanol. The filtrate was concentrated and the residue was dissolved in a mixture of tetrahydrofuran/water (25 mL/5 mL). LiOH (660 mg, 28.0 mmol) was added and the resulting mixture was stirred at room temperature over 3 days. The tetrahydrofuran was removed in 25 vacuo and the aqueous residue was treated with 4N hydrochloric acid carefully until pH 5-6. The mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC and then recrystallized from methanol/water to afford the title compound as a white solid (1.21 g, 65%). MS (ES+) m/z 508 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.12 - 1.24 (m, 2 H), 1.34 - 1.43 (m, 11 30 H), 1.55 (m, 2 H), 2.14 - 2.28 (m, 1 H), 2.65 (s, 3 H), 3.89 - 3.98 (m, 2 H), 4.73 (d, J=6.98 Hz, 2 H), 8.09 (d, J=1.07 Hz, 1 H), 8.39 (s, 1 H), 8.55 - 8.64 (m, 1 H). 396 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of tert-butyl 4-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-l)-2H tetrazol-2-yl)methyl)piperidine-1 -carboxylate F N O CI N N 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (141 mg, 0.37 5 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinic acid (100 mg, 0.25 mmol), (3-chloro-4-fluorophenyl)methanamine (47 mg, 0.30 mmol), and triethylamine (0.05 mL, 0.37 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC. The product was dissolved in methanol, passed through a carbonate cartridge, 10 and concentrated to afford the title compound as a solid (59 mg, 43%). LCMS (ES+) m/z 544 (M+H). Step 3: Preparation of N-(3-chloro-4-fluorobenzvl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5 yl)picolinamide F 0 -- HN Cl N- NH N N A vial was charged with tert-butyl 4-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6 15 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)piperidine- 1 -carboxylate (59 mg, 0.12 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0.5 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then passed through a carbonate cartridge eluting with methanol and concentrated to afford the title compound as a solid (49 mg, 95%). MS (ES+) m/z 444 (M+H). 'H NMR (400 MHz, CDC1 3 ) 6 ppm 1.38 - 1.53 (m, 2 H), 1.69 (s, J=12.08 Hz, 2 20 H), 2.20 - 2.34 (m, 1 H), 2.60 - 2.72 (m, 5 H), 3.17 - 3.25 (m, 2 H), 4.57 (d, J=6.98 Hz, 2 H), 4.63 (d, J=6.44 Hz, 2 H), 7.10 (t, J=8.59 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.41 (dd, J=6.98, 2.15 Hz, 1 H), 8.05 (d, J=1.34 Hz, 1 H), 8.46 (t, J=6.31 Hz, 1 H), 8.70 (s, 1 H). Example 388 N-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol 25 5-yl)picolinamide 397 WO 2009/016498 PCT/IB2008/002046 F N 0 Cl N" N -~- N'r S 0 Methane sulfonylchloride (0.007 mL, 0.08 mmol) was added to a mixture of N-(3-chloro-4 fluorobenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazo-5-yl)picolinamide (prepared as described in Example 387) (25 mg, 0.06 mmol) and triethylamine (0.016 mL, 0.11 mmol) in dichloromethane (1 5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The residue was dissolved in methanol and passed through a carbonate cartridge. Concentration of the resulting solution afforded the title compound as a solid (16 mg, 55%). MS (ES+) m/z 522 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.01 - 1.27 (m, 3 H), 1.51 (d, J=1 1.71 Hz, 2 H), 10 1.93 - 2.10 (m, 2 H), 2.51 - 2.60 (m, 1 H), 2.65 (s, 3 H), 3.05 - 3.16 (m, 1 H), 3.38 (d, J=11.71 Hz, 3 H), 4.33 (d, J=5.86 Hz, 2 H), 4.60 (d, J=7.32 Hz, 2 H), 7.18 (d, J=7.32 Hz, 2 H), 7.31 - 7.44 (m, J=8.05 Hz, 1 H), 7.90 (s, 1 H), 8.24 (s, 1 H), 9.18 (t, J=6.59 Hz, 1 H). Example 389 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5 15 yl)picolinamide F - N O F N~ F F N / I NH -- N Step 1: Preparation of terf-butyl 4-((5-(2-((4-fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)piperidine-1 -carboxylate F 0 F -F HN N - N' N!- NN 0 20 2-(1 H-Benzotriazole- 1 -yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinic acid (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl) 6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide, Example 387) (100 mg, 0.25 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)methanamine (58 mg, 0.30 mmol), and triethylamine (0.05 mL, 0.37 25 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by reverse phase preparative HPLC. The product was 398 WO 2009/016498 PCT/IB2008/002046 dissolved in methanol, passed through a carbonate cartridge, and concentrated to afford the title compound as a solid (61 mg, 43%). LCMS (ES+) m/z 578 (M+H). Step 2: Preparation of N-(4-fluoro-3-(trifluoromethyl)benzvl)-6-methyl-4-(2-(piperidin-4-vlmethyl)-2H tetrazol-5-yl)picolinamide F N F - H F HN NI F F N NH N 5 A vial was charged with tert-butyl 4-((5-(2-((4-fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)piperidine- 1 -carboxylate (63 mg, 0.12 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0.5 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then passed through a carbonate cartridge 10 eluting with methanol and concentrated to afford the title compound as a solid (49 mg, 100%). MS (ES+) m/z 478 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.11 - 1.24 (m, 3 H), 1.50 (d, J=1 1.72 Hz, 2 H), 2.04 - 2.17 (m, 1 H), 2.42 - 2.50 (m, 2 H), 2.64 (s, 3 H), 2.95 (d, J=11.72 Hz, 2 H), 4.54 (d, J=7.33 Hz, 2 H), 4.66 (d, J=5.86 Hz, 2 H), 7.34 - 7.49 (m, 1 H), 7.63 - 7.79 (m, J=19.78, 6.59 Hz, 2 H), 8.05 (s, 1 H), 8.38 (s, 1 H), 9.39 (t, J=6.59 Hz, 1 H). 15 Example 390 N-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)methyl) 2H-tetrazol-5-yl)picolinamide F 0 F HN F N- N FF N /I N" I - NN I 0 Methane sulfonylchloride 0.006 mL, 0.07 mmol) was added to a mixture of N-(4-fluoro-3 20 (trifluoromethyl)benzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 389) (23 mg, 0.05 mmol) and triethylamine (0.013 mL, 0.10 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The residue was dissolved in methanol and passed through a carbonate 25 cartridge. Concentration of the resulting solution afforded the title compound as a solid (16 mg, 58%). MS (ES+) m/z 556 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.19 - 1.43 (m, 3 H), 1.67 (d, J=1 1.71 Hz, 2 H), 2.08 - 2.24 (m, 2 H), 2.66 - 2.75 (m, 2 H), 2.81 (s, 3 H), 3.54 (d, J=1 1.71 Hz, 3 H), 4.55 (d, J=5.86 Hz, 2 H), 4.75 (d, J=7.32 Hz, 2 H), 7.38 - 7.51 (m, 1 H), 7.64 - 7.81 (m, 2 H), 8.06 (s, 1 H), 8.40 (s, 1 H), 9.40 (t, J=6.22 Hz, 1 H). 399 WO 2009/016498 PCT/IB2008/002046 Example 391 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazo-5-yl)picolinamide F- - HN 0 0 N N NH NN I NH -- NN Step 1: Preparation of tert-butyi 4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-vl) 5 2H-tetrazol-2-yl)methyl)piperidine-1 -carboxylate F- - HN 0 N NNN N O W O 2-(1 H-Benzotriazole- 1 -yl)-1, 1, 3,3-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinic acid (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl) 10 6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide, Example 387) (100 mg, 0.25 mmol), 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N (4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4 carboxamide, Example 1) (46 mg, 0.30 mmol), and triethylamine (0.05 mL, 0.37 mmol) in N,N dimethylformamide (2 mL), and the mixture was stirred at room temperature for 18 hours. The 15 reaction mixture was purified by reverse phase preparative HPLC. The product was dissolved in methanol, passed through a carbonate cartridge, and concentrated to afford the title compound as a solid (63 mg, 47%). MS (ES+) m/z 540(M+H). Step 2: Preparation of N-(4-fluoro-3-methoxvbenzvl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol 5-yl)picolinamide F 0
-
N' 20 A vial was charged with tert-butyl 4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)piperidine-1-carboxylate (53 mg, 0.10 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0.5 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then passed through a carbonate cartridge 25 eluting with methanol and concentrated to afford the title compound as a solid (43 mg, 100%). MS (ES+) m/z 440 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.07 - 1.26 (m, 3 H), 1.49 (d, J= 11.72 Hz, 2 H), 2.03 - 2.18 (m, 2 H), 2.44 - 2.52 (m, 2 H), 2.65 (s, 3 H), 2.94 (d, J=11.72 Hz, 2 H), 3.80 (s, 3 H), 400 WO 2009/016498 PCT/IB2008/002046 4.48 (d, J=7.33 Hz, 2 H), 4.67 (d, J=5.86 Hz, 2 H), 6.85 - 6.93 (m, 1 H), 7.04 - 7.22 (m, 2 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.21 (t, J=5.86 Hz, 1 H). Example 392 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H 5 tetrazol-5-yl)picolinamide F N N HN N /N N" - NN 0 Methane sulfonylchloride 0.006 mL, 0.07 mmol) was added to a mixture of N-(4-fluoro-3 methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 391) (20 mg, 0.05 mmol) and triethylamine (0.013 mL, 0.10 mmol) in 10 dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The residue was dissolved in methanol and passed through a carbonate cartridge. Concentration of the resulting solution afforded the title compound as a solid (15 mg, 61%). MS (ES+) m/z 518 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) d ppm 1.18 - 1.43 (m, 3 H), 1.67 (d, J=1 1.71 15 Hz, 2 H), 2.09 - 2.24 (m, 2 H), 2.62 - 2.76 (m, 2 H), 2.81 (s, 3 H), 3.54 (d, J=12.45 Hz, 3 H), 3.80 (s, 3 H), 4.48 (d, J=5.86 Hz, 2 H), 4.76 (d, J=6.59 Hz, 2 H), 6.82 - 6.92 (m, 1 H), 7.05 - 7.20 (m, 2 H), 8.06 (s, 1 H), 8.41 (s, 1 H), 9.22 (t, J=6.22 Hz, 1 H). Example 393 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-morpholin-2-ylmethyl)-2H-tetrazol-5 20 yl)picolinamide F 0 -P HN -0 ~ N N - N 401 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of (2R)-tert-butvl 2-((5-(2-((4-fluoro-3-methoxybenzyl)carbamovi)-6-methylpyridin 4-yl)-2H-tetrazol-2-yl)methyl)morpholin e-4-carboxylate F 0 00 -P ~HN -" -0 NN N -- N A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared 5 as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (0.070 g, 0.19 mmol), (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.050 g, 0.23 mmol), and polymer supported-triphenylphosphine (0.60 g, 0.29 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to 0 *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.053 g, 0.23 mmol) was added. 10 The mixture was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography (0-2% methanol/dichloromethane) to afford the title compound as a beige oil (65 mg, 62%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.58 min, m/z 564 (M+Na). Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-morpholin-2-vimethyl)-2H 15 tetrazol-5-yl)picolinamide F N H NN Trifluoroacetic acid (0.5 mL) was added to a solution of (2R)-tert-butyl 2-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)morpholine-4-carboxylate in dichloromethane (2 mL), and the mixture was stirred for 1 hour at room temperature. The reaction 20 mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title compound. Example 394 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-4-acetylmorpholin-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide 402 WO 2009/016498 PCT/IB2008/002046 F N O0 -O N N ) Triethylamine (0.037 mL, 0.26 mmol) and a solution of acetyl chloride (13 mg in 0.5 mL dichloromethane) were added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 393) (0.065 g, 5 0.12 mmol) in dichloromethane (2 mL). The mixture was stirred for 1 hour at room temperature and then was concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (26 mg, 45%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (br. s., 1 H), 8.41 (br. s., 1 H), 8.06 (br. s., 1 H), 7.13 (dd, J=23.4, 10.3 Hz, 1 H), 6.89 (d, J=5.1 Hz, 1 H), 4.82 - 5.04 (m, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 4.37 (d, J=1 1.7 Hz, 1 H), 3.97 (br. s., 2 H), 3.80 10 (s, 3 H), 3.61 (br. s., 1 H), 3.39 (br. s., 1 H), 3.11 (br. s., 1 H), 2.66 (s, 5 H), 2.01 (d, J=16.1 Hz, 3 H). Example 395 N-(4-FIuoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholiin-2-ylmethyl)-2H-tetrazol-5 yl)picolinamide F - HN O H -O NzN N N
-
N 15 Step 1: Preparation of (2S)-tert-butyl 2-((5-(2-((4-fluoro-3-methoxvbenzyl)carbamoyl)-6-methylpyridin 4-yl)-2H-tetrazol-2-vl)methyl)morpholine-4-carboxylate F 0 -O N N N N \ -~~ N'N O A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 20 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (0.070 g, 0.19 mmol), (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.050 g, 0.23 mmol), and polymer supported-triphenylphosphine (0.60 g, 0.29 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to 0 *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.053 g, 0.23 mmol) was added. The mixture was allowed to warm to room temperature while stirring over 15 hours. The reaction 25 mixture was filtered and the filtrate was concentrated. The residue was purified by silica column 403 WO 2009/016498 PCT/IB2008/002046 chromatography (0-2% methanol/dichloromethane) to afford the title compound as a beige oil (63 mg, 61%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 5.57 min, m/z 564 (M+Na). Step 2: Preparation of N-(4-fluoro-3-methoxybenzvl)-6-methyl-4-(2-((S)-morpholin-2-ylmethvl)-2H tetrazol-5-yl)picolinamide F 0 -P HN H -O NzN N N NX- NK~~ 0 'N 5 Trifluoroacetic acid (0.5 mL) was added to a solution of (2S)-tert-butyl 2-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)morpholine-4-carboxylate in dichloromethane (2 mL), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title 10 compound. Example 396 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)4-acetylmorpholin-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F N O -O NazN N - HN N \ \ O 15 Triethylamine (0.037 mL, 0.26 mmol) and a solution of acetyl chloride (13 mg in 0.5 mL dichloromethane) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 395) (0.063 g, 0.12 mmol) in dichloromethane (2 mL). The mixture was stirred for 1 hour at room temperature and then was concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % 20 acetonitrile/water) to afford the title compound (29 mg, 50%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.21 (d, J=5.9 Hz, 1 H), 8.41 (br. s., 1 H), 8.06 (br. s., 1 H), 7.05 - 7.22 (m, 2 H), 6.80 - 6.95 (m, 1 H), 4.80 - 5.08 (m, 2 H), 4.48 (d, J=6.6 Hz, 3 H), 4.37 (d, J=13.9 Hz, 1 H), 3.90 - 4.15 (m, 2 H), 3.80 (s, 3 H), 3.63 (d, J=13.2 Hz, 1 H), 3.33 - 3.47 (m, 1 H), 3.02 - 3.20 (m, 1 H), 2.66 (s, 3 H), 2.02 (d, J=16.8 Hz, 3 H). 25 Example 397 N-(4-Fluoro-3-methoxybenzyl)-6-methyl4-(2-(((R)4-(methylsulfonyl)morpholin-2-yl)methyl)-2H tetrazol-5-yl)picolinamide 404 WO 2009/016498 PCT/IB2008/002046 F O 0 O::// ~ HN
S
-O N N N Nx - ~ N' fO) Triethylamine (0.037 mL, 0.26 mmol) and a solution of methanesulfonyl chloride (18 mg in 0.5 mL dichloromethane) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S) morpholin-2-ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 395) (0.075 g, 5 0.18 mmol) in dichloromethane (2 mL). The mixture was stirred for 1 hour at room temperature and then was concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (18 mg, 20%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 8.07 (s, 1 H), 7.06 - 7.22 (m, 2 H), 6.89 (br. s., 1 H), 5.04 (dd, J=14.3, 3.3 Hz, 1 H), 4.91 (dd, J=13.9, 8.1 Hz, 1 H), 4.48 (d, J=6.6 Hz, 2 H), 4.06 - 4.17 (m, 1 H), 3.89 10 (d, J=12.4 Hz, 1 H), 3.80 (s, 3 H), 3.67 (d, J=11.7 Hz, 1 H), 3.44 - 3.55 (m, 1 H), 3.32 (d, J=11.0 Hz, 1 H), 2.91 (s, 3 H), 2.73 - 2.88 (m, 2 H), 2.66 (s, 3 H). Example 398 N-(3-Methoxybenzyl)-6-methyl4-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5-yl)picolinamide N O H -O N N N N x -- N' O 15 Step 1: Preparation of (2S)-tert-butyl 2-((5-(2-((3-methoxvbenzvl)carbamovl)-6-methylpyridin-4-vl)-2H tetrazol-2-yl)methyl)morpholine-4-carboxylate 0 - HN -O N N N \ A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 20 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (0.75 g, 2.3 mmol), (S)-tert-butyl 2 (hydroxymethyl)morpholine-4-carboxylate (0.53 g, 2.4 mmol), and polymer supported triphenylphosphine (1.29 g, 2.77 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to 0 0C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.80 g, 3.5 mmol) was added. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica column 25 chromatography (0-2% methanol/dichloromethane) to afford the protected amine as a beige oil. 405 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2-ylmethyl)-2H-tetrazol-5 yl)picolinamide - N O H -O N N N NN Trifluoroacetic acid (1.0 mL) was added to a solution of (2S)-tert-butyl 2-((5-(2-((3 5 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)morpholine-4-carboxylate in dichloromethane (5 mL), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title compound. The reaction mixture was diluted with dichloromethane (10 mL) and neutralized to pH 7 with a 2.5 N aqueous solution of sodium hydroxide. The organic phase was separated and washed 10 with water (10 mL) followed by brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (0.43 g, 44%). Example 399 N-(3-Methoxybenzyl)-4-(2-(((S)-4-acetylmorpholin-2-yl)methyl)-2H-tetrazo-5-yl)-6 methylpicolinamide HN O O 1 -0 NN N Nx 15 Triethylamine (0.037 mL, 0.26 mmol) and a solution of acetyl chloride (17 mg in 0.5 mL dichloromethane) was added to a solution of N-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2 ylmethyl)-2H-tetrazol-5-yl)picolinamide (prepared as described in Example 398) (0.075 g, 0.18 mmol) in dichloromethane (2 mL). The mixture was stirred for 1 hour at room temperature and then was 20 concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (44 mg, 54%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=5.9 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.95 - 5.04 (m, 1 H), 4.85 - 4.95 (m, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 3.90 - 4.13 (m, 2 H), 3.79 (d, J=10.3 Hz, 1 H), 3.71 (s, 3 H), 3.43 (d, J=9.5 Hz, 1 H), 3.05 - 3.20 (m, 2 H), 2.62 - 2.73 (m, 4 25 H), 2.01 (d, J=16.8 Hz, 3 H). Example 400 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide 406 WO 2009/016498 PCT/IB2008/002046 0 0 -- HN -O NzN N Triethylamine (0.022 mL, 0.16 mmol) and a solution of methanesulfonyl chloride (15 mg in 0.5 mL dichloromethane) was added to a solution of N-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2 ylmethyl)-2H-tetrazol-5-y)picolinamide (prepared as described in Example 398) (0.045 g, 0.11 mmol) 5 in dichloromethane (2 mL). The mixture was stirred for 1 hour at room temperature and then was concentrated. The residue was purified by silica column chromatography (0-75%ethyl acetate/heptane) to afford the title compound (20 mg, 37%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.42 (s, 1 H), 8.07 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=7.3 Hz, 1 H), 4.98 - 5.09 (m, 1 H), 4.91 (dd, J=14.6, 8.1 Hz, 1 H), 4.49 (d, J=6.6 Hz, 2 H), 4.11 (d, 10 J=9.5 Hz, 1 H), 3.89 (d, J=11.7 Hz, 1 H), 3.71 (s, 3 H), 3.67 (d, J=11.0 Hz, 1 H), 3.50 (t, J=10.3 Hz, 1 H), 3.32 (d, J=11.7 Hz, 1 H), 2.91 (s, 3 H), 2.75 - 2.88 (m, 2 H), 2.66 (s, 3 H). Example 401 rac-4-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-methoxybenzyl)-6 methylpicolinamide F 0 -P HN -O N N O N I N 15 rac-2-(lodomethyl)-1,4-dioxane (57 mg, 0.25 mmol) was added to a mixture of N-(4-fluoro-3 methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide, Example 170) (79 mg, 0.23 mmol) and triethylamine (23 mg, 0.23 mole) in 20 anhydrous acetonitrile (1 mL). The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (39 mg). MS (ES+) m/z 443 (M+H). 'H NMR (400 MHz, 25 DMSO-d 6 ) 6 ppm 9.24 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.10-7.24 (m, 2 H), 6.91 (br s, 1 H), 4.85-4.95 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (m, 1 H), 3.85-3-95 (m, 1 H), 3.82 (s, 3 H), 3.30-3-80 (m, 5 H), 2.68 (s, 3 H). Example 402 rac-4-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-N-(4-fluoro-3-methylbenzyl)-6 30 methylpicolinamide 407 WO 2009/016498 PCT/IB2008/002046 F z 0- F N N"\ N1 O N -- -N 0 rac-2-(lodomethyl)-1,4-dioxane (114 mg, 0.5 mmol) was added to a mixture of N-(4-fluoro-3 methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as describe in step 1 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazo-5-y)-6 5 methylpicolinamide, Example 185) (150 mg, 0.46 mmol) and triethylamine (46 mg, 0.46 mmol) in anhydrous acetonitrile (2 mL). The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried with ether, decanted, and dried in a vacuum desiccator to 10 afford the title compound as a white solid (61 mg). MS (ES+) m/z 427 (M+H). IH NMR (400 MHz, DMSO-de) 6 ppm 9.24 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.00-7.30 (m, 3 H), 4.85-4.95 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (m, 1 H), 3.85-3-95 (m, 1 H), 3.30-3-80 (m, 5 H), 2.68 (s, 3 H), 2.20 (s, 3 H). Example 403 15 rac-N-(3-M ethoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxyethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol 5-yi)-6-methylpicolinamide HN -O / N N x OOH - N'W rac-((2R*,5R*)-5-(Hydroxymethyl)- 1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 20 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide, Example 61) (1.4 g, 4.3 mmol) was added to a mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (1.0 g, 3.1 mmol) and triethylamine (0.4 g, 4.0 mmole) in anhydrous N,N-dimethylacetamide (1 mL). The mixture was stirred 25 at 85*C in a capped vial overnight and then was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (1.04 g). MS (ES+) m/z 455 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 30 Hz, 1 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.80-4.95 (m, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.15 (m, 1 H), 3.99 (dd, J=11.3, 1.8 Hz, 1 H), 3.77 (d, J=11.3Hz, 1 H), 3.73 (s, 3 H), 3.30-3.50 (m, 4 H), 2.68 (s, 3 H). 408 WO 2009/016498 PCT/IB2008/002046 Example 404 N-(3-Methoxybenzyl)-4-(2-(((2S,5R)-5-(hydroxym ethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazo-5-yl) 6-methylpicolinamide 0 -N O -O N" sN 0N 0 OH N 5 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 403) was separated by chiral supercritical-fluid chromatography (AS-H, 30 x 250 mm, 20% methanol, 70 mL/min) and the first eluting isomer was isolated to afford the title compound (50 mg). MS (ES+) m/z 455 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 10 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.80-4.95 (m, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.15 (m, 1 H), 3.99 (dd, J=11.3, 1.8 Hz, 1 H), 3.77 (d, J=11.3 Hz, 1 H), 3.73 (s, 3 H), 3.30-3-50 (m, 4 H), 2.68 (s, 3 H). Example 405 N-(3-Methoxybenzyl)-4-(2-(((2R,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazo-5-yl) 15 6-methylpicolinamide
-
\
-
N N OH rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide (prepared as described in Example 403) was separated by chiral supercritical-fluid chromatography (AS-H, 30 x 250 mm, 20% methanol, 70 mL/min) and the second 20 eluting isomer was isolated to afford the title compound (50 mg). MS (ES+) m/z 455 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.80-4.95 (m, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.15 (m, 1 H), 3.99 (dd, J=1 1.3, 1.8 Hz, 1 H), 3.77 (d, J=1 1.3 Hz, 1 H), 3.73 (s, 3 H), 3.30-3-50 (m, 4 H), 2.68 (s, 3 H). 25 Example 406 rac-(2S*,5S*)-Methyl 5-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)-1,4-dioxane-2-carboxylate 409 WO 2009/016498 PCT/IB2008/002046 N HN O N_ 0 0 -O N-N O0 rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2-carboxylate, Example 85) (1.22 g, 3.7 5 mmol) was added to a mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (1.2 g, 3.7 mmol) and triethylamine (749 mg, 7.4 mmol) in anhydrous N,N-dimethylacetamide (2.3 mL). The mixture was stirred at 850C in a capped vial overnight and then was purified by reverse phase preparative HPLC 10 (water/acetonitrile) to afford the title compound as a white solid (1.7 g). Example 407 rac-(2S*,5S*)-5-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)-1,4-dioxane-2-carboxylic acid -0 N 0 -N/ \ I~ 0 '_, N O OH 15 Sodium hydroxide (10 pellets) was added to rac-(2S*,5S*)-methyl 5-((5-(2-((3-methoxybenzyl) carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate (prepared as described in Example 406) (1.35 g, 2.8 mmol) in a mixture of tetrahydrofuran/water (6 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse-phase preparative HPLC (water/ acetonitrile). The resulting 20 product was slurried and decanted from ether several times and dried in a vacuum desiccator to afford the title compound as a white solid (1.09 g). MS (ES+) m/z 469 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.85-4.99 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (s, 3 H), 3.90-3.99 (m, 1 H), 3.73 (s, 3 H), 3.45-3-60 (m, 2 H), 2.68 (s, 3 H). 25 Example 408 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hydroxypropan-2-yl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide 410 WO 2009/016498 PCT/IB2008/002046
-HN
N OI -- O NI NN OO ~~- N 0 A solution of methyl magnesium iodide (3M in ether, 0.16 mL, 0.48 mmol) was added dropwise at room temperature to a solution of rac-(2S*,5S*)-methyl 5-((5-(2-((3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2-carboxylate 5 (prepared as described in Example 406) (75 mg, 0.15 mmol) in anhydrous tetrahydrofuran (1 mL). Additional tetrahydrofuran (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to ice bath temperature and saturated aqueous ammonium chloride solution (0.5 mL) was added dropwise. The product was purified by reverse phase preparative HPLC (water/ acetonitrile). Fractions containing the product were passed through a 10 carbonate resin column and the filtrate was concentrated. The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (25 mg). MS (ES+) m/z 483 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.80 4.99 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.00-4.15 (m, 2 H), 3.90-3.99 (m, 1 H), 3.73 (s, 3 H), 3.33-3.45 15 (m, 2 H), 3.12-3.19 (m, 1 H), 2.68 (s, 3 H), 1.07 (s, 3 H), 1.01 (s, 3 H). Example 409 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-y) - - 6-methylpicolinamide -\ 0 - N N N N NH 2 --- N'N . O 20 Formamide (300 mg) was added to a solution of rac-(2S*,5S*)-methyl 5-((5-(2-((3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol- 2 -yl)methyl)-1,4-dioxane-2-carboxylate (prepared as described in Example 406) (149 mg, 0.3 mmol) in anhydrous tetrahydrofuran (3 mL) at reflux temperature. A solution of sodium methoxide (25% in methanol, 300 mg) was added and the mixture was stirred at reflux for 1.5 hours. The reaction mixture was purified by reverse phase 25 preparative HPLC (water/ acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (106 mg). MS (ES+) m/z 468 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.83 (d, J=1.5 Hz, 1 H), 4.85 30 4.99 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (m, 3 H), 3.90-3.99 (m, 1 H), 3.73 (s, 3 H), 3.45-3-60 (m, 2 H), 2.68 (s, 3 H). 411 WO 2009/016498 PCT/IB2008/002046 Example 410 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide N H N NN O CN N \ 5 Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 300 mg) was added to rac-N (3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (Example 409) (85 mg, 0.18 mmol) in a mixture of carbon tetrachloride (0.5 mL) and dichloroethane (4.5 mL) and the mixture was heated at 80 *C for 3 hours. The reaction mixture was filtered and the 10 resin was washed with dichloroethane. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC. Fractions containing the first eluting isomer were passed through a carbonate resin column and were concentrated. The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (23 mg). MS (ES+) m/z 450 (M+H). 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.29 (t, J=6.4 Hz, 1 H), 15 8.44 (s, 1 H), 8.11 (s, 1 H), 7.25 (t, J=8.1 Hz, 1 H), 6.90 - 6.94 (m, 2 H), 6.83 (dd, J=8.1, 2.0 Hz, 1 H), 5.04 (d, J=2.7 Hz, 1 H), 4.99 (br. s., 1 H), 4.97 (d, J=3.6 Hz, I H), 4.51 (d, J=6.3 Hz, 2 H), 4.24 - 4.31 (m, 1 H), 4.08 (dd, J=11.9, 2.6 Hz, 1 H), 3.95 (d, J=12.5 Hz, 1 H), 3.81 (dd, J=12.5, 3.2 Hz, 1 H), 3.74 (s, 3 H), 3.71 - 3.75 (m, 1 H), 2.69 (s, 3 H). Example 411 20 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5R*)-5-cyano-1,4-dioxan-2.yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide N H N sN OCN N'N o Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 410 afforded the title compound as a white solid (24 mg). MS (ES+) 25 m/z 450 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.4 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.87 - 6.93 (m, 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.92 - 5.02 (m, 2 H), 4.77 (dd, J=8.4, 2.9 Hz, 1 H), 4.49 (d, J=6.2 Hz, 2 H), 4.21 - 4.30 (m, 1 H), 4.05 - 4.13 (m, 2 H), 3.71 (s, 3 H), 3.64 (ddd, J=22.0, 12.0, 8.4 Hz, 2 H), 2.66 (s, 3 H). 412 WO 2009/016498 PCT/IB2008/002046 Example 412 rac-N-(4-Fluoro-3-methoxybenzyl)4-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide F 0 - HN N - N O 0 5 rac-((2R*,5R*)-5-(Hydroxymethyl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl) 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidfine-4-carboxamide, Example 61) (3.03 g, 10.0 mmol) was added to a mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5 yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2 10 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (1.9 g, 5.0 mmol) and triethylamine (2.8 g, 27.0 mmol) in anhydrous DMA (3 mL). The mixture was stirred at 90*C in a capped vial overnight. The reaction mixture is allowed to cool, diluted with excess dichloromethane, and washed with 2N aqueous sodium hydroxide solution (2x) and water (4x). The organic layer was concentrated and the residue was crystallized from a mixture of methanol/ethyl 15 acetate (70/30) over 48 hours in a refrigerator to afford the title compound as a white solid (1.03 g). MS (ES+) m/z 473 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.10-7.24 (m, 2 H), 6.91 (br. s. 1 H), 4.80-4.95 (m, 2 H), 4.65 (t, J=5.7 Hz, 1 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.15 (m, 1 H), 3.99 (dd, J=11.3, 1.8 Hz, 1 H), 3.77 (d, J=11.3 Hz, 1 H), 3.82 (s, 3 H), 3.30-3-50 (m, 4 H), 2.68 (s, 3 H). 20 Example 413 rac-(2S*,5S*)-Methyl 5-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F 0 O -O / N O- O -I N0 N-~ "\'10 rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1,4-dioxane-2-carboxylate (prepared as described 25 in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)-l1,4-dioxane-2-carboxylate, Example 85) (77 mg, 0.23 mmol) was added to a mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5 yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2 (((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (80 mg, 30 0.23 mmol) and triethylamine (24 mg, 0.23 mmol) in anhydrous acetonitrile (2 mL). The mixture was stirred at 80*C in a capped vial overnight and then was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (65 mg). 413 WO 2009/016498 PCT/IB2008/002046 Example 414 rac-(2S*,5S*)-5-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol 2-yl)methyl)-1,4-dioxane-2-carboxylic acid F N O N ND\ O< 0" OH - N - N-s.\ ( 0 5 Sodium hydroxide (2 pellets) was added to rac-(2S*,5S*)-methyl 5-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate (prepared as described in Example 413) (65 mg, 0.13 mmol) in a mixture of tetrahydrofuran/water (1 mL, 1/1) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse-phase preparative HPLC (water/ acetonitrile). 10 The resulting product was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (50 mg). MS (ES+) m/z 487 (M+H). IH NMR (400 MHz, DMSO-d) 6 ppm 9.24 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.10-7.24 (m, 2 H), 6.91 (br. S., 1 H), 4.85-4.99 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (m, 3 H), 3.90-3.99 (m, 1 H), 3.82 (s, 3 H), 3.45-3-60 (m, 2 H), 2.68 (s, 3 H). 15 Example 415 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S)-5-(2-hydroxypropan-2-yl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F N 0 F- HN 0 N I OH - NN A solution of methyl magnesium iodide (3M in ether, 0.1 mL, 0.3 mmol) was added dropwise 20 at room temperature to a solution of rac-(2S*,5S*)-methyl 5-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate (prepared as described in Example 413) (35 mg, 0.07 mmol) in anhydrous tetrahydrofuran (1 mL). Additional tetrahydrofuran (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to ice bath temperature and saturated aqueous ammonium 25 chloride solution (0.5 mL) was added dropwise. The product was purified by reverse phase preparative HPLC (water/ acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (21 mg). MS (ES+) m/z 501 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.2 Hz, 1 30 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.1-7.25 (m, 2 H), 6.91 (br. s., 1 H), 4.80-4.99 (m, 2 H, in), 4.52 (d, J=6.2 Hz, 2 H), 4.00-4.15 (m, 2 H), 3.90-3.99 (m, 1 H), 3.82 (s, 3 H), 3.33-3.45 (m, 2 H), 3.12-3.19 (m, 1H), 2.68 (s, 3 H), 1.07 (s, 3H), 1.01 (s, 3H). 414 WO 2009/016498 PCT/IB2008/002046 Example 416 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide F N 0 -P HN 0 -0 / \ N N N O NH 2 --- N-N O' 5 Formamide (200 mg) was added to a solution of rac-(2S*,5S*)-methyl 5-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate (prepared as described in Example 413) (123 mg, 0.3 mmol) in anhydrous tetrahydrofuran (1.5 mL) at reflux temperature. A solution of sodium methoxide (25% in methanol, 200 mg) was added and the mixture was stirred at reflux for 1.5 hours. The reaction mixture was purified by reverse phase 10 preparative HPLC (water/ acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (78 mg). MS (ES+) m/z 486 (M+H). 1 H NMR (400 MHz, DMSO-de) 6 ppm 9.24 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.10-7.24 (m, 2 H), 6.91 (br. S., 1 H), 4.85-4.99 (m, 2 H), 4.52 (d, J=6.2 15 Hz, 2 H), 4.05-4.20 (m, 3 H), 3.90-3.99 (m, 1 H), 3.82 (s, 3 H), 3.45-3-60 (m, 2 H), 2.68 (s, 3 H). Example 417 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide F N 0 N 0 20 Polymer supported triphenylphosphine (Argonaut; 2.15 mmol/g, 200 mg) was added to rac-N (4-fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (Example 416) (65.2 mg, 0.13 mmol) in a mixture of carbon tetrachloride (0.25 mL) and dichloroethane (2.25 mL) and the mixture was heated at 80 *C for 3 hours. The reaction mixture was filtered and the resin was washed with dichloroethane. The filtrate was concentrated and the 25 residue was purified by reverse phase preparative HPLC. Fractions containing the first eluting isomer were passed through a carbonate resin column and were concentrated. The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (23 mg). MS (ES+) m/z 468 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.31 (t, J=6.3 Hz, 1 H), 8.44 (s, 1 H), 8.11 (d, J=1.0 Hz, 1 H), 7.19 (dd, J=9.1, 2.5 Hz, 1 H), 7.15 (dd, 30 J=1 1.7, 8.4 Hz, 1 H), 6.87 - 6.94 (m, 1 H), 5.04 (d, J=2.7 Hz, 1 H), 4.99 (br. s., 1 H), 4.97 (d, J=4.1 Hz, 415 WO 2009/016498 PCT/IB2008/002046 1 H), 4.51 (d, J=6.3 Hz, 2 H), 4.23 - 4.31 (m, 1 H), 4.08 (dd, J=11.9, 2.6 Hz, 1 H), 3.95 (d, J=12.5 Hz, 1 H), 3.83 (s, 3 H), 3.71 - 3.82 (m, 2 H), 2.69 (s, 3 H). Example 418 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-cyano-1,4-dioxan-2-yl)methyl)-2H-tetrazol 5 5-yi)-6-methylpicolinamide F 0 O HN N HN - NN CN N Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 417 afforded the title compound as a white solid (18 mg). MS (ES+) m/z 468 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.0 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 10 H), 7.87 (s, 1 H), 7.16 (d, J=8.1 Hz, 1 H), 7.11 (dd, J=1 1.5, 8.2 Hz, 1 H), 6.85 - 6.91 (m, 1 H), 4.74 5.00 (m, 2 H), 4.48 (d, J=6.2 Hz, 2 H), 4.05 - 4.17 (m, 2 H), 4.02 (d, J=8.1 Hz, 1 H), 3.89 (dd, J=1 1.5, 2.7 Hz, 1 H), 3.80 (s, 3 H), 3.62 - 3.72 (m, 1 H), 2.65 (s, 3 H). Example 419 rac-N-(4-Fluoro-3-methoxybenzyl)4-(2-(((2S*,5S*)-5-(2-hydroxyacetyl)-1,4-dioxan-2-yl)methyl) 15 2H-tetrazol-5-yl)-6-methylpicolinamide F 0 - HN O
--
~ N'N 0 OH N I - N Ny,. ' Oxalyl chloride (10 mL) was added to a stirred solution of rac-(2S*,5S*)-5-((5-(2-((4-fluoro-3 methoxybenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylic acid (prepared as described in Example 414) (820 mg, 1.69 mmol) in dichloromethane (10 mL). The 20 mixture was stirred at room temperature for 18 hours and then concentrated. The residue was repeatedly taken up in dichloromethane and concentrated to remove excess oxalyl chloride. The resulting residue was then taken up in dioxane (5 mL) and treated with tris(trimethylsiloxy)ethylene (5.0 g, 17.0 mmol). The mixture was heated to 95*C for 18 hours. Additional tris(trimethylsiloxy)ethylene (5.0 g, 17.0 mmol) was added and heating at 950C was continued for 1 25 week. The mixture was treated with several drops of 3 N hydrochloric acid until gas evolution stopped. The reaction mixture was purified by reverse phase preparative HPLC. Fractions containing desired product were combined and concentrated. The residue was dissolved in methanol and passed through a carbonate cartridge. The filtrate was concentrated to afford the title compound as a solid (29 mg, 3%). MS (ES+) m/z 501 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 2.66 (s, 3 H), 3.43 30 - 3.58 (m, 2 H), 3.63 (s, 2 H), 3.80 (s, 3 H), 3.90 - 4.00 (m, 1 H), 4.02 - 4.19 (m, 2 H), 4.19 - 4.27 (m, 1 416 WO 2009/016498 PCT/IB2008/002046 H), 4.48 (d, J=5.86 Hz, 2 H), 4.79 - 4.99 (m, 3 H), 6.83 - 6.94 (m, 1 H), 7.06 - 7.20 (m, 2 H), 8.06 (br. s., 1 H), 8.41 (br. s., 1 H), 9.16 - 9.26 (m, 1 H). Example 420 rac-(2S*,5S*)-Methyl 5-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-y)-2H 5 tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate F 0 O N xN1N O O - N rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)- 1,4-dioxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2 methylpyrimidin-4-yl)-2H-tetrazol-2-yl)methyl)- 1,4-d ioxane-2-carboxylate, Example 85) (83 mg, 0.25 10 mmol) was added to a mixture of N-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 1 of the synthesis of N-(3-chloro-4-fluorobenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinam ide, Example 194) (75 mg, 0.22 mmol) and triethylamine (109 mg, 1.0 mmol) in anhydrous N,N-dimethylacetamide (0.3 mL). The mixture was stirred at 85*C in a capped vial overnight and then was purified by reverse phase preparative 15 HPLC (water/acetonitrile) to afford the title compound as a white solid (99 mg). Example 421 rac-(2S*,5S*)-5-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)-1,4-dioxane-2-carboxylic acid F 0 O - HN_ CIN sN O OH \\"( - N'N 0 20 Sodium hydroxide (3 pellets) was added to rac-(2S*,5S*)-methyl 5-((5-(2-((3-chloro-4 fluorobenzyl)carbamoyl)-6-methylpyridin-4-y)-2H-tetrazol-2-yl)methyl)- 1,4-dioxane-2-carboxylate (prepared as described in Example 420) (99 mg, 0.2 mmol) in a mixture of tetrahydrofuran/water (0.8 mL, 1/1) and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with trifluoroacetic acid and purified by reverse-phase preparative HPLC (water/acetonitrile). 25 The resulting product was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (68 mg). MS (ES+) m/z 491 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.36 (t, J=6.0 Hz, 1 H), 8.42 (s, 1 H), 8.09 (s, 1 H), 7.55-7.6 (m, I H), 7,35-7.45 (m, 2 H), 4.85-4.99 (m, 2 H), 4.52 (d, J=6.2 Hz, 2 H), 4.05-4.20 (m, 3 H), 3.90-3.99 (m, 1 H), 3.45-3-60 (m, 2 H), 2.68 (s, 3 H). 417 WO 2009/016498 PCT/IB2008/002046 Example 422 rac-N-(3 -Methoxybenzyl)-4-(2-(((2R*,5S*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5 yi)-6-methylpicolinamide 0 H HN -0 N NN N N N O NH2 -- NO 5 Step 1: Preparation of rac-((2R*,5R*)-5-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H tetrazol-2-yl)methvl)- 1,4-dioxan-2-yl)methyl methanesulfonate N O O -O NzN O N P02\ - NN , O O Methane sulfonyl chloride (172 mg, 1.5 mmol) was added to a solution of rac-N-(3 methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-y)-6 10 methylpicolinamide (prepared as described in Example 403) (620 mg, 1.36 mmol) in anhydrous pyridine (2 ml) at 0 *C. The mixture was allowed to stir at room temperature overnight. The reaction mixture was cooled to 0 *C, diluted with water, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to afford the title compound (546 mg). Step 2: Preparation of rac-N-(3-methoxybenzl)-4-(2-(((2R*,5S*)-5-(aminomethyl)-1,4-dioxan-2 15 yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide - HN O -O N\ N. ONNH N 'NH 2 Concentrated ammonium hydroxide (50 mg, 1.40 mmol) was added to a solution of rac ((2R*,15R)-5-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)-1,4 dioxan-2-yl)methyl methanesulfonate (140 mg, 0.263 mmol) in tetrahydrofuran (5 mL) and the mixture 20 was heated to 100 *C overnight. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (25 mg, 16%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.690 min., m/z 568 (M+H). 'H NMR (400 MHz, methanol-d 4 ) 6 ppm 2.65 - 2.69 (m, 2 H), 2.78 - 2.90 (m, 2 H), 2.94 - 3.10 (m, 2 H), 3.32 - 3.46 (m, 1 H), 3.55 - 3.68 (m, 1 H), 3.74 - 3.77 (m, 3 H), 3.78 - 3.84 (m, 1 H), 4.07 - 4.14 (m, 1 H), 4.17 - 4.27 (m, 1 H), 4.56 25 4.63 (m, 2 H), 6.81 (dd, J=7.79, 2.15 Hz, 1 H), 6.77 - 6.83 (m, 1 H), 6.90 - 6.96 (m, 2 H), 7.22 (t, J=8.19 Hz, 1 H), 8.09 (s, 1 H), 8.56 (s, 1 H). 418 WO 2009/016498 PCT/IB2008/002046 Example 423 rac-N-(3-M ethoxybenzyl)-6-methyl-4-(2-((2R*,5S*)-5-(methylsulfonamidomethyl)-1,4-dioxan-2 yl)methyl)-2H-tetrazol-5-yl)picolinamide N O -- N N -- IN'N , O H O 5 Diisopropylethylamine (157 mg, 1.21 mmol) was added to a solution of rac-N-(3 methoxybenzyl)-4-(2-(((2R*,5S*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 422) (55 mg, 0.12 mmol) in N,N dimethylformamide (5.0 mL). After 20 minutes, methanesulfonyl chloride (69.5 mg, 0.606 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was 10 concentrated, and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (36.4 mg, 46%). LCMS (5%-95% CH 3
CN/H
2 0, 5 min.) 4.923 min., m/z 532 (M+H). 'H NMR (400 MHz, DMSO-d6) 6 ppm 2.66 (s, 3 H), 2.87 (s, 3 H), 2.94 (t, J=5.86 Hz, 3 H), 3.46 (d, J=10.98 Hz, 4 H), 3.42 (br. s., 1 H), 3.71 (s, 3 H), 3.76 (d, J=1 1.71 Hz, 3 H), 4.49 (d, J=6.59 Hz, 4 H), 4.78 - 4.94 (m, 5 H). 15 Example 424 rac-N-(3-Methoxybenzyl)-4-(2-(((2R*,5S*)-5-(acetamidomethyl)-1,4-dioxan-2-yl)methyl)-2H tetrazol-5-yl)-6-methylpicolinamide - N O -o N .N O. N N I NN - N'N O H Diisopropylethylamine (0.45 mL, 0.97 mmol) was added to a solution of rac-N-(3 20 methoxybenzyl)-4-(2-(((2R*,5S*)-5-(aminomethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide (prepared as described in Example 422) (55 mg, 0.12 mmol) in N,N dimethylformamide (5.0 mL). After 20 minutes, acetic anhydride (0.34 mL, 0.364 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by reverse phase preparative HPLC to afford the title compound as a 25 solid (36.7 mg, 50%). LC/MS (5%-95% CH 3
CN/H
2 0, 5 min.) 3.17 min., m/z 496 (M+H). 'H NMR (400 MHz, DMSO-d) 6 ppm 1.78 (s, 3 H), 2.49 (s, 1 H), 2.67 (s, 1 H), 2.97 - 3.08 (m, 1 H), 3.38 - 3.51 (m, 3 H), 3.65 - 3.75 (m, 4 H), 3.92 - 4.02 (m, 2 H), 4.02 - 4.09 (m, 2 H), 4.44 - 4.53 (m, 3 H), 4.75 - 4.95 (m, 4 H), 6.76 - 6.82 (m, 1 H), 6.85 - 6.93 (m, 1 H), 7.16 - 7.26 (m, 1 H), 7.78 - 7.89 (m, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H), 9.12 - 9.25 (m, 1 H). 30 Example 425 N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydrofuran-2-yl)methyl)-2H-tetrazol-5-yl)picolinamide 419 WO 2009/016498 PCT/IB2008/002046 HN -O N N 0 Di-tert-butylazodicarboxylate (74.0 mg, 0.320 mmol) was added to a cooled (ice bath) mixture of (tetrahydrofuran-2-yl)methanol (32.68 mg, 0.320 mmol), N-(3-methoxybenzyl)-6-methyl-4-(2H tetrazol-5-yl)picolinamide (52.0 mg, 0.160 mmol) (prepared as described in step 5 of the synthesis of 5 N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153), and triphenylphosphine resin (186.0 mg, 0.400 mmol, 2.15 mmol/g loading) in anhydrous tetrahydrofuran (3 mL). The mixture was allowed to warm to room temperature and agitated overnight. Trifluoroacetic acid (2 mL) was added and the mixture was agitated for 1 hour. The reaction mixture was filtered and the resin was washed with trifluoroacetic acid (1 mL). The 10 filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95%
CH
3
CN/H
2 0, 8 min.) to afford the title compound as a solid (30.8 mg, 47%). LC/MS (5%-95%
CH
3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.198 min., m/z 409 (M+H). Example 426 N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-tetrazo1-5 15 yl)picolinamide F N 0 N O - HNN 4-(Bromomethyl)-tetrahydro-2H-pyran (90 mg, 0.5 mmol) was added to a mixture of N-(4 fluoro-3-methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as describe in step 1 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 20 methylpicolinamide, Example 185) (150 mg, 0.46 mmol) and triethylamine (46 mg, 0.46 mmol) in anhydrous acetonitrile (2 mL). The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile). Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated. The residue was slurried with ether, decanted, and dried in a vacuum desiccator to 25 afford the title compound as a white solid (135 mg). MS (ES+) m/z 425 (M+H). Example 427 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide 420 WO 2009/016498 PCT/IB2008/002046 HNO -O N N x -X t NO NN To a vial containing tetrahydropyran-2-methanol (0.348 mL, 3.08 mmol), a solution of N-(3 methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 5 methylpicolinamide, Example 153) (500.0 mg, 1.54 mmol) in anhydrous tetrahydrofuran (25 mL) and triphenylphosphine resin (1.791 g, 3.85 mmol, 2.15 mmol/g loading) was added. The reaction mixture was chilled in an ice bath, and di-tert-butylazodicarboxylate (709.0 mg, 3.08 mmol) was added. The ice bath was removed and the reaction mixture was agitated (orbital) overnight at room temperature. Volatiles were removed under a nitrogen stream. The residue was purified by silica gel 10 chromatography to afford the title compound as a solid (350 mg, 54%). LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN,1.5 min.): 3.506 min., m/z 423 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.23 (m, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.23 - 7.19 (m, 1 H), 6.89 - 6.87 (m, 2 H), 6.80 - 6.77 (m, 1 H), 4.79 - 4.74 (m, 2 H), 4.48 (d, J=6.0 Hz, 2 H), 3.93 - 3.75 (m), 3.70 (s, 3 H), 2.65 (s, 3 H), 1.80 1.25 (m). 15 Example 428 (-)-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide N O -0 - N N 0 N \ /\ I -O NO rac-N-(3-Methoxybenzyl)-6-imethyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 20 yl)picolinamide was resolved by supercritical fluid chromatography (Chiralcel OD-H, 30 x 250 mm, 25/75 ethanol/CO 2 , 70 mL/min) to afford the title compound as an oil (0.25 g). Chiralcel OD-H analytical column (4.6 x 250 mm; 20/80, ethanol/CO 2 ), 8.06 min, > 99% ee; [a]D 21 *c = 22.70.(c = 8.3, DMF). Example 429 25 (+)-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide 421 WO 2009/016498 PCT/IB2008/002046 HN O -O N N rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide was resolved by supercritical fluid chromatography (Chiralcel OD-H, 30 x 250 mm, 25/75 ethanol/CO 2 , 70 mL/min) to afford the title compound as an oil (0.26 g). Chiralcel OD-H 5 analytical column (4.6 x 250 mm; 20/80, ethanol/CO 2 ), 9.99 min, > 99% ee; [aD.
21 C = 190.(c = 9.8, DMF). Example 430 rac-N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol 5-yl)picolinamide F 0 - HN 10 Step 1: Preparation of methyl 6-methyl-4-(2-((tetrahvdro-2H-pyran-2-vl)methyl)-2H-tetrazol-5 yl picolinate 0 0 \O - NN Methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the 15 synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 153) (0.50 g, 2.0 mmol), tetrahydropyran-2- methanol (0.27 g, 2.28 mmol), and polymer supported-triphenylphosphine (2.65 g, 5.70 mmol) were suspended in tetrahydrofuran (100 mL). The mixture was cooled to O 0C in an ice bath for 15 min and then di-tert butyl azodicarboxylate (1.05 g, 4.56 mmol) was added. The reaction was allowed to warm to room 20 temperature and was stirred for 15 hours. The mixture was filtered through a CeliteTm pad and washed with tetrahydrofuran (15 mL). The filtrate was concentrated and purified by silica gel column chromatography (0-50 % ethyl acetate/hexanes) to afford the title compound as an oil (0.58 g, 81%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 4.88 min, m/z 318 (M+H). 422 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of 6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-vl)picolinic acid 0 HO - NN N / -N N 6-Methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)picolinate (0.54 g, 1.84 mmol) was dissolved in tetrahydrofuran (5 mL) and then treated with an aqueous sodium hydroxide 5 solution (2.5 N). The mixture was stirred at ambient temperature for 2 hours and then the tetrahydrofuran was removed in a stream of nitrogen. The aqueous residue was acidified to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (0.48 g, 86%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 3.88 min, m/z 304 (M+H). 10 Step 3: Preparation of rac-N-(4-fluoro-3-methoxybenzvl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2 yl)methyl)-2H-tetrazol-5-yl)picolinamide F N - HN0 -O N NN 1-Hydroxybenzatriazole (22 mg, 0.16 mmol) was added to a solution of 6-methyl-4-(2 ((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)picolinic acid (0.035g, 0.12 mmol) in N,N 15 dimethylformamide (0.5 mL). After being stirred for 5 min, N-methylmorpholine (0.051 mL, 0.46 mmol) was then added followed by a solution of 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4 aminocyclohexyl)methyl)-2H-tetrazo-5-yl)pyrimidine-4-carboxamide, Example 1) (18 mg, 0.12 mmol) in N,N-dimethylformamide (0.5 mL). 1 -Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (31 20 mg, 0.16 mmol) was then added. The mixture was stirred at room temperature for 18 hours and then purified by reverse phase preparative HPLC to afford the title compound as an oil (6.5 mg, 13%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.06 (s, 1 H), 7.21 - 7.06 (m, 2 H), 6.89 (s, 1 H), 4.72 - 4.86 (m, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.92 (dd, J=11.0, 5.1 Hz, 1 H), 3.84 3.74 (m, 3 H), 2.66 (s, 3 H), 1.80 (d, J=12.5 Hz, 2 H), 1.71 (d, J=1 1.7 Hz, 2 H), 1.58 - 1.16 (m, 4 H). 25 Example 431 rac-N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyrafn-2-yl)methyl)-2H-tetrazol-5 yl)picolinamide 423 WO 2009/016498 PCT/IB2008/002046 F O N I NN o 1 -Hydroxybenzatriazole (22 mg, 0.16 mmol) was added to a solution of 6-methyl-4-(2 ((tetrahydro-2H-pyran-2-yl)m ethyl)-2H-tetrazol-5-yl)picolinic acid (prepared as described in step 2 of the synthesis of rac-N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl) 5 2H-tetrazol-5-yl)picolinamide, Example 430) (0.035g, 0.12 mmol) in N,N-dimethylformamide (0.5 mL). After being stirred for 5 min, N-methylmorpholine (0.051 mL, 0.46 mmol) was then added followed by a solution of (4-fluoro-3-methylphenyl)methanamine ( 16 mg, 0.12 mmol) in N,N-dimethylformamide (0.5 mL). 1 -Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) was then added. The mixture was stirred at room temperature for 18 hours and then purified by reverse phase 10 preparative HPLC to afford the title compound as an oil (5.1 mg, 10%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.18 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.06 (s, 1 H), 7.20 (t, J=8.1 Hz, 1 H), 6.87 (s, 2 H), 6.77 (d, J=8.8 Hz, 1 H), 4.68 - 4.90 (m, 2 H), 4.48 (d, J=6.6 Hz, 2 H), 3.86 - 4.06 (m, 4 H), 3.78 (d, J=1 1.0 Hz, 1 H), 2.65 (s, 3 H), 1.75 (dd, J=34.8, 12.8 Hz, 2 H), 1.13 - 1.58 (m, 4 H). Example 432 15 rac-N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-3-yl)methyl)-2H-tetrazol 5-yl)picolinamide F 0 -_P HN -O N N N O Step 1: Preparation of rac-(tetrahydro-2H-Dyran-3-vl)methanol HO 0 20 Tetrahydro-2H-pyran-3-carbaldehyde (0.40 g, 3.5 mmol) was dissolved in anhydrous methanol (7 mL) and cooled to -10 *C. Sodium borohydride (0.53 g, 14 mmol) was added in three portions. The reaction was stirred 1 hour at 0 *C and was then quenched with a saturated aqueous solution of ammonium chloride (5 mL). The mixture was filtered and the filtrate was concentrated to aqueous in vacuo without heat. The residue was then diluted with water (5 mL) and ethyl acetate (15 25 mL), and the mixture was again filtered, The filtrate was transferred to a separatory funnel and the phases separated. The aqueous layer was re-extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with water (4 x 10 mL) followed by brine (10 mL), dried over sodium sulfate, and concentrated at 30 *C under vacuum to afford the title compound as an oil (0.31 g, 76%). LC/MS (5-100% CH 3
CN/H
2 0, 8 min) 0.85 min, m/z 117 (M+H). 424 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of rac-(tetrahydro-2H-pyran-3-yl)methyl 4-nitrobenzenesulfonate 0 0 110 0-- /NO 2 0 4-Nitrobenzene-1-sulfonyl chloride (0.62 g, 2.8 mmol) and pyridine (253 mg, 3.20 mmol) were added to a solution of rac-(tetrahydro-2H-pyran-3-yl)methanol (0.31 g, 2.67 mmol) in dichloromethane 5 (5 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane (10 mL) and washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, and concentrating. The residue was purified on silica gel column chromatography (0 50% ethyl acetate/heptane) to afford the title compound as an oil (0.65 g, 81%). LC/MS (5-100%
CH
3
CN/H
2 0, 5 min) 2.56 min, m/z 302 (M+H). 10 Step 3: Preparation of rac-N-(4-fluoro-3-methoxvbenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-3 yI)methyl)-2H-tetrazol-5-yl)picolinamide F 0 F- HN 0 -O - N2N N A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 15 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (79 mg, 0.23 mmol), rac-(tetrahydro-2H-pyran-3-yl)methyl 4-nitrobenzenesulfonate (77 mg, 0.25 mmol), and triethylamine (0.40 mL) in N,N-dimethylacetamide (0.1 mL) was stirred at 85 *C for 15 hours. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a beige solid (68 mg, 69%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8.08 (s, 1 H), 7.12 20 (d, J=8.4 Hz, 1 H), 7.16 (dd, J=13.4, 8.2 Hz, 2 H), 6.91 (d, J=4.0 Hz, 1 H), 4.74 (dd, J=12.6, 7.1 Hz, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.82 (s, 3 H), 3.72 (t, J=12.4 Hz, 2 H), 3.39 (t, J=9.0 Hz, 1 H), 2.68 (s, 3 H), 2.28 (br. s., 1 H), 1.74 (d, J=12.4 Hz, 1 H), 1.63 (d, J=4.0 Hz, 1 H), 1.49 (dd, J=9.5, 4.0 Hz, 1 H), 1.35 (d, J=9.5 Hz, 1 H). Example 433 25 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-3-yl)methyl)-2H-tetrazol-5 yl)picolinamide
-HN
-0 ~ O -O - N N NO A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 425 WO 2009/016498 PCT/IB2008/002046 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (79 mg, 0.23 mmol), rac-(tetrahydro-2H-pyran-3 yl)methyl 4-nitrobenzenesulfonate (prepared as described in step 2 of the synthesis of rac-N-(4-fluoro 3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-3-yl)methyl)-2H-tetrazol-5-yl)picolinamide, Example 432) (77 mg, 0.25 mmol), and triethylamine (0.40 mL) in N,N-dimethylacetamide (0.1 mL) 5 was stirred at 85 *C for 15 hours. The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a beige solid (62 mg, 61%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.20 (br. s., 1 H), 8.08 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.82 (d, J=7.7 Hz, 1 H), 4.75 (dq, J=13.0, 6.8 Hz, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 3.73 (s, 5 H), 3.68 (br. s., 1 H), 3.41 (br. s., 1 H), 3.37 (d, J=2.2 Hz, 1 H), 2.68 (s, 3 H), 2.28 (br. s., 1 H), 1.74 (br. s., 1 H), 1.62 (br. s., 1 H), 1.50 (d, 10 J=8.8 Hz, 1 H), 1.35 (d, J=9.5 Hz, 1 H). Example 434 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide F N 0 F- - HN -O - N N OH N\ N 15 Step 1: Preparation of rac-(3R*,6S*)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-oI 0 ,\OH HO OH Tetrabutylammonium fluoride (23.0 g, 88.0 mmol) was added to a suspension of rac (3R*,6S*)-6-((tert-butyldiphenylsilyloxy)methyl)-tetrahydro-2H-pyran-3-ol (Bioorg. Med. Chem. 2006, 14, 3953-3966) (16.3 g, 44.0 mmol) in tetrahydrofuran (700 mL). The mixture was allowed to stir at 20 room temperature for 6 hours and was then concentrated. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 2/1; ethyl acetate/ethanol, 40/1). The crude product was further purified by silica gel chromatography (ethyl acetate) to afford a waxy solid which was repeatedly triturated with chloroform and then filtered to provide the title compound as a white solid (2.44 g, 42%). 25 Step 2: Preparation of rac-N-(4-fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-hydroxy-tetrahvdro-2H pyran-2-l)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F 0 O -P HN -O - N N OH N O A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 426 WO 2009/016498 PCT/IB2008/002046 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (1.50 g, 3.96 mmol), rac-(3R*,6S*)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (1.05 g, 7.92 mmol), and polymer supported triphenylphosphine resin (3.68 g, 7.92 mmol) in tetrahydrofuran (20 mL) was cooled in an ice bath. Di tert-butyl-azodicarboxylate (1.82 g, 7.92 mmol) was added and the resulting mixture was stirred in the 5 ice bath for 30 min. The ice bath was removed and the mixture stirred at room temperature for 18 hours. Trifluoroacetic acid (5 mL) was added and the reaction mixture was filtered. The resin washed with tetrahydrofuran, methanol, and acetonitrile. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (251 mg, 11%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.27 - 1.47 (m, 2 H), 1.78 - 1.88 (m, 1 H), 1.93 - 2.04 (m, 10 1 H), 2.68 (s, 3 H), 2.90 (t, J=10.25 Hz, 1 H), 3.37 - 3.47 (m, 1 H), 3.68 - 3.77 (m, 1 H), 3.78 - 3.92 (m, 4 H), 4.51 (d, J=6.59 Hz, 2 H), 4.74 - 4.93 (m, 3 H), 6.85 - 6.95 (m, 1 H), 7.08 - 7.24 (m, 2 H), 8.08 (s, 1 H), 8.43 (s, 1 H), 9.24 (t, J=6.22 Hz, 1 H). Example 435 N-(4-Fluoro-3-methoxybenzyl)-4-(2-((1 S*,2S*,4R*)-7-oxa-bicyclo[2.2.1]heptan-2-ylmethyl)-2H 15 tetrazol-5-yl)-6-methylpicolinamide F N O NN Step 1: Preparation of (1S*,2S*,4R*)-7-oxa-bicvclo[2.2.llheptan-2-vlmethanol HOJ A mixture of (1 S*,2R*,4R*)-7-oxa-bicyclo[2.2.1 ]heptane-2-carboxylic acid (J. Med. Chem. 20 1971, 14, 698-702) (0.25 g, 1.8 mmol) and carbodiimidazole ( 0.29 g, 1.8 mmol) in tetrahydrofuran (5 mL) was stirred for 15 minutes. A solution of sodium borohydride (0.11 g, 2.8 mmol) in water (1 mL) was slowly added and the mixture was allowed to stir at room temperature for 15 hours. The reaction mixture was diluted with an aqueous 10% hydrochloric acid solution (2 mL) and brine (2 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 25 mL), dried over sodium sulfate and concentrated to afford the title compound as an oil. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 3.29 (br. s., 1 H), 2.94 - 3.13 (m, 2 H), 1.68 - 1.82 (m, 2 H), 1.40 - 1.60 (m, 4 H), 1.28 - 1.40 (m, 2 H), 0.89 - 1.01 (m, 1 H). 427 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-4-(2-((1S*,2S*,4R*)-7-oxa-bicyclo[2.2.1lheptan-2 ylmethyl)-2H-tetrazol-5-yl)-6-methylpicolinamide F N -O N N\ A mixture of (1S*,2S*,4R*)-7-oxa-bicyclo[2.2.1]heptan-2-ylmethanol (0.13 g, 0.98 mmol), N-(4 5 fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl)-2H-tetrazol-5 yl)-6-methylpicolinamide, Example 170) (0.31 g, 0.81 mmol), and polymer supported triphenylphosphine (0.58 g, 1.22 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to 0*C in an ice bath for 15 minutes. Di-tert-butyl azodicarboxylate (0.23 g, 0.98 mmol) was added and the mixture 10 was allowed to warm to room temperature and stir for 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to afford the title compound as a beige oil (66 mg, 18%). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.08 - 9.26 (m, 1 H), 8.40 (br. s., 1 H), 8.05 (br. s., 1 H), 7.05 - 7.21 (m, 2 H), 6.88 (br. s., 1 H), 4.64 (dd, J=13.18, 8.05 Hz, 1 H), 4.42 - 4.56 (m, 4 H), 4.33 (d, J=5.12 Hz, 1 H), 3.79 (s, 3 15 H), 3.22 (br. s., 1 H), 2.64 (s, 3 H), 1.63 (dd, J=11.35, 8.42 Hz, 1 H), 1.49 - 1.57 (m, 2 H), 1.38 - 1.48 (m, 2 H), 1.34 (d, J=13.18 Hz, 1 H). Example 436 Ethyl 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)bicyclo[2.2.2]octane-1 -carboxylate _\ 0 - HN O -0 N N O \'"
-
I N 20 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (130 mg), ethyl 4 ((tosyloxy)methyl)bicyclo[2.2.2]octane-1-carboxylate (J. Amer. Chem. Soc. 1965, 87, 2404) (147 mg), 25 and diisopropylethylamine (0.090 mL) in dimethylsulfoxide (2.0 mL) was heated to 115 *C for 5 days. The reaction mixture was purified by reverse phase preparative HPLC (acetonitrile/water, 70/30 90/10). Fractions containing the product were concentrated and extracted with dichloromethane (3 x 8 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound (118 mg). MS (ES+) m/z 519 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 30 9.20 (t, J=6.4 Hz, I H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.88 - 6.92 (m, 2 H), 6.80 (d, J=8.4 Hz, 1 H), 4.54 (s, 2 H), 4.49 (d, J=6.2 Hz, 2 H), 3.98 (q, J=7.0 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 1.63 - 1.71 (m, 6 H), 1.43 - 1.50 (m, 6 H), 1.11 (t, J=7.0 Hz, 3 H). 428 WO 2009/016498 PCT/IB2008/002046 Example 437 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid HN O O - HN -O N a~N~NO 5 Water (0.5 mL) and lithium hydroxide-monohydrate (21.4 mg) was added to a solution of ethyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)bicyclo[2.2.2]octane-1-carboxylate (prepared as described in Example 436) (75 mg) in tetrahydrofuran (1.0 mL). The mixture was heated at reflux for 3 days and then allowed to cool to room temperature. The reaction mixture was filtered and the pH was adjusted to 4 with 1N aqueous 10 hydrochloric acid. The resulting slurry was filtered, washed with water, and dried to afford the title compound as a white solid (54 mg). MS (ES+) m/z 491 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.87 - 6.92 (m, 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.54 (s, 2 H), 4.49 (d, J=6.6 Hz, 2 H), 3.71 (s, 3 H), 2.65 (s, 3 H), 1.61 - 1.70 (m, 6 H), 1.41 - 1.50 (m, 6 H). 15 Example 438 N-(3-Methoxybenzyl)-4-(2-((4-(hydroxymethyl)bicyclo[2.2.2]octan-1 -yl)methyl)-2H-tetrazol-5-yl) 6-methylpicolinamide SHN -O N NzN N \ OH A solution of 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 20 yl)methyl)bicyclo[2.2.2]octane-1-carboxylic acid (prepared as described in Example 437) (102 mg) in 2-methyltetrahydrofuran (5 mL) was cooled in an ice bath and a solution of lithium aluminum hydride (1 M in tetrahydrofuran, 0.30 mL) was added. After 5 minutes the reaction was quenched with water. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (2 x 3 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The 25 residue was purified by reverse phase preparative HPLC to afford the title compound (30.7 mg). MS (ES+) m/z 477 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.2 Hz, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (dd, J=7.7, 1.5 Hz, 1 H), 4.47 - 4.53 (m, 4 H), 4.24 (t, J=5.5 Hz, 1 H), 3.71 (s, 3 H), 2.99 (d, J=5.1 Hz, 2 H), 2.65 (s, 3 H), 1.26 - 1.45 (m, 12 H). 429 WO 2009/016498 PCT/IB2008/002046 Example 439 4-(2-((4-(Hydroxymethyl)pentacyclo[4.2.0.0 5 .0'''.0 4 7 ]oct-1 -yl)methyl)-2H-tetrazo-5-yl)-N-(3 methoxybenzyl)-6-methylpyridine-2-carboxamide HN0 N -O N x 'N OH 5 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (52 mg, 0.16 mmol), 1,4 bis(hydroxymethyl)cubane (J. Amer. Chem. Soc. 1991, 113, 7692) (52 mg, 0.32 mmol), and polymer supported triphenylphosphine (190 mg, 0.4 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled in 10 an ice bath and di-tert-butyl azodicarboxylate (74 mg, 0.32 mmol) was added. The mixture was placed in an ultrasonic bath for 10 min and then filtered. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (14.6 mg). MS (ES+) m/z 471 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.24 (t, J=6.4 Hz, 1 H), 8.38 (s, 1 H), 8.04 (s, 1 H), 7.2 (t, J= 8.1 Hz, 1 H), 6.88 (s, 2 H), 6.78 (d, J=8.1 Hz, 1 H), 5.01 (s, 2 H), 4.46 (d, J=6.2 Hz, 3 H), 15 3.79 - 3.74 (m, 3 H), 3.71 - 3.64 (m, 6 H), 3.46 (d, J=5.5 Hz, 2 H), 2.63 (s, 3 H). Example 440 4-((5-(2-(((3-Methoxybenzyl)amino)carbonyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cubane-1-carboxylic acid HN 0 0 -O /\ NN OH N \ 20 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (155 mg), methyl 4 hydroxymethylcubanecarboxylate (136 mg), and polymer supported triphenylphosphine (453 mg) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice bath and di-terf-butyl azodicarboxylate (165 25 mg) was added. The mixture was placed in an ultrasonic bath for 30 min and then filtered. The filtrate was acidified with trifluoroacetic acid (0.5 mL) and then concentrated. The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20). The fractions containing product were concentrated and extracted with methylene chloride (3 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white 30 solid (146 mg). MS (ES+) m/z 485 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 12.26 (S, 1 H), 9.24 (t, J=6.4 Hz, 1 H), 8.39 (s, 1 H), 8.05 (d, J=1.3 Hz, 1 H), 7.21 (t, J=8.1 Hz, 1 H), 6.87 - 6.90 (m, 2 H), 430 WO 2009/016498 PCT/IB2008/002046 6.79 (dd, J=8.1, 2.1 Hz, 1 H), 5.06 (s, 2 H), 4.47 (d, J=6.4 Hz, 2 H), 4.01 - 4.05 (m, 3 H), 3.88 - 3.92 (m, 3 H), 3.70 (s, 3 H), 2.65 (s, 3 H). Example 441 4-(2-((4-(Aminocarbonyl)pentacyclo[4.2.0.0 2 ,.0a.s.0 4 ]oCt-1 -yl)methyl)-2H-tetrazol-5-yl)-N-(3 5 methoxybenzyl)-6-methylpyridine-2-carboxamide HN O 0 -O NzN
NH
2 N \ I
--
\ N 4-((5-(2-(((3-Methoxybenzyl )amino)carbonyl)-6-methylpyridin-4-yl)-2H-tetrazol-2 yl)methyl)cubane-1-carboxylic acid (prepared as described in Example 440) (92 mg) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen and oxalyl chloride (0.100 mL) was added followed 10 by N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in anhydrous tetrahydrofuran (4.0 mL) and a solution of 7N ammonia in methanol (0.30 mL) was added in one portion. The mixture was diluted with water (5 mL), acidified with trifluoroacetic acid, and concentrated. The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 40/60 - 65/35) to afford the title compound as a 15 white solid (52 mg). MS (ES+) m/z 484 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, J=6.0 Hz, 1 H), 8.43 (s, 1 H), 8.07 (s, 1 H), 7.24 (t, J=8.1 Hz, I H), 7.17 (br. s., 1 H), 6.93 (br. s., 2 H), 6.87 (br. s., 1 H), 6.82 (d, J=6.2 Hz, 1 H), 5.07 (s, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 4.00 - 4.05 (m, 3 H), 3.86 3.91 (m, 3 H), 3.73 (s, 3 H), 2.68 (s, 3 H). Example 442 20 4-(2-((4-Cyanopentacyclo[4.2.0.0 2
,
5 .0 3 '$ .0 4
'
7 joct-I -yl)methyl)-2H-tetrazol-5-y)-N-(3 methoxybenzyl)-6-methylpyridine-2-carboxamide 0 - HN N -O NN N \ N Phosphorus oxychloride (0.030 mL) was added to a solution of 4-(2-((4-(aminocarbonyl) pentacyclo[4.2.0.0 2
,
5 .0 3
.
8 .0 4
'
7 ]oct-1-yl)methyl)-2H-tetrazol-5-yl)-N-(3-methoxybenzyl)-6-methylpyridine 25 2-carboxamide (prepared as described in Example 441) (32 mg) in DMF (0.8 mL). The mixture was stirred for 2 minutes and then a solution of 5% aqueous sodium bicarbonate (2 mL) was slowly added. The liquid was decanted and the solid was stirred with water (2 mL) and placed in an ultrasonic bath for 1 hour. The resulting slurry was filtered, washed with water, and dried to afford the title compound as a white solid (26 mg). MS (ES+) m/z 466 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.22 (t, 30 J=5.5 Hz, 1 H), 8.42 (s, 1 H), 8.06 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 (br. s., 2 H), 6.82 (d, J=8.4 Hz, 431 WO 2009/016498 PCT/IB2008/002046 1 H), 5.09 (s, 2 H), 4.51 (d, J=6.2 Hz, 2 H), 4.25 - 4.29 (m, 3 H), 4.01 - 4.06 (m, 3 H), 3.73 (s, 3 H), 2.68 (s, 3 H). Example 443 N-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-3-methylbutan-2-yl)-2H-tetrazol-5-yl)picolinamide HNO -O N N N -_ N~ NN 5 A mixture of N-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 5 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((trans)-4-aminocyclohexyl)methyl) 2H-tetrazol-5-yl)-6-methylpicolinamide, Example 153) (100 mg, 0.31 mmol), polymer supported triphenylphosphine (287 mg, 0.62 mmol), and (R)-(-)-3-methyl-2-butanol(54 mg, 0.62 mmol) in 10 tetrahydrofuran (100 mL) was cooled to 0 *C and di-tert-butyl azodicarboxylate (142 mg, 0.62 mmol) was added. The mixture was allowed to warm to room temperature and stir for 18 hours. The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (hexane/EtOAc, 8/1; 4/1). Fractions containing product were concentrated and further purified by reverse phase preparative HPLC 15 (acetonitrile/water, 0.05% TFA, 15/85 - 85/15). Combined fractions were neutralized with 2.5 N NaOH solution and acetonitrile was removed in vacuo. The remaining aqueous solution was extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (16 mg, 13%). MS (ES+) m/z 395 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.26 (t, J=6.4 Hz, 1 H), 8.43 (d, J=0.9 Hz, 1 H), 8.09 (d, J=1.1 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.90 20 6.93 (m, 2 H), 6.82 (ddd, J=8.2, 2.5, 0.8 Hz, 1 H), 4.95 (qd, J=6.9, 6.8 Hz, 1 H), 4.51 (d, J=6.4 Hz, 2 H), 3.73 (s, 3 H), 2.68 (s, 3 H), 2.31 - 2.18 (m, 1 H), 1.62 (d, J=6.9 Hz, 3 H), 0.97 (d, J=6.9 Hz, 3 H), 0.78 (d, J=6.7 Hz, 3 H). Example 444 N-(4-Fluoro-3-methoxybenzyl)-4-(2-((R)-3-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl)-6 25 methylpicolinamide -FHN -O NaN OH N A mixture of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (45 mg, 0.13 mmol), 30 (S)-(+)-3-bromo-2-methyl-1-propanol (33 mL, 0.20 mmol), and triethylamine (33 mL, 0.24 mmol) in 432 WO 2009/016498 PCT/IB2008/002046 acetonitrile (3 mL) was stirred at 80 *C for 15 hours. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to afford the title compound as a beige solid (35 mg, 65%). 1 H NMR (400 MHz, DMSO-d 6 ) J ppm 9.12 - 9.34 (m, 1 H), 8.45 (s, 1 H), 8.19 (s, 1 H), 8.05 (s, 1 H), 7.90 (s, 1 H), 7.06 - 7.21 (m, 2 H), 6.88 (d, J=7.3 Hz, 1 H), 4.59 (dd, J=14.3, 6.2 Hz, 1 5 H), 4.49 (d, J=5.9 Hz, 2 H), 4.31 (dd, J=13.9, 8.1 Hz, 1 H), 3.80 (s, 3 H), 3.32 (s, 1 H), 2.65 (d, J=3.7 Hz, 3 H), 2.02 - 2.22 (m, 1 H), 0.75 (d, J=6.6 Hz, 3 H). Example 445 N-(4-Fluoro-3-methoxybenzyl)4-(2-((S)-3-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl)-6 methylpicolinamide F 0 -P HN_ -O N N OH N 10 A mixture ofN-(4-fluoro-3-methoxybenzyl)-6-methyl4-(2H-tetrazol-5-yl)picolinamide(prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((trans)-4 aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide, Example 170) (45 mg, 0.13 mmol), (R)-(-)-3-bromo-2-inethyl-1-propanol (33 mL, 0.20 mmol), and triethylamine (33 mL, 0.24 mmol) in 15 acetonitrile (3 mL) was stirred at 80 *C for 15 hours. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to afford the title compound as a beige solid (38 mg, 70%). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.12 - 9.33 (m, 1 H), 8.19 (s, 1 H), 7.90 (s, 1 H), 7.02 - 7.24 (m, 2 H), 6.89 (d, J=5.86 Hz, 1 H), 4.59 (dd, J=14.3, 6.2 Hz, 1 H), 4.48 (d, J=5.9 Hz, 2 H), 4.31 (dd, J=14.3, 7.7 Hz, 1 H), 3.80 (s, 3 H), 3.29 (s, 1 H), 2.62 - 2.74 (m, 3 H), 2.52 (s, 2 H), 2.11 (dd, 20 J=13.5, 6.2 Hz, 1 H), 0.75 (d, J=6.6 Hz, 3 H). Example 446 N-(4-Fluoro-3-methylbenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinamide F N 0 HN Step 1: preparation methyl 4(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinate 0 0 / / \ NN N 25 A suspension of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of N-3mtoyezl--2((rn)4aioylhxlmty)2-erzl5y)6 433 WO 2009/016498 PCT/IB2008/002046 methylpicolinamide, Example 153) (1.00 g, 4.56 mmol), 2-methylpropan-1-ol (0.34 g, 4.6 mmol), and polymer supported-triphenylphosphine (3.04 g, 6.84 mmol) in anhydrous tetrahydrofuran (25 mL) was cooled to O *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (1.26 g, 5.47 mmol) was added. The mixture was allowed to warm to room temperature while stirring over 15 hours. The 5 reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica chromatography (0-50% ethyl acetate:/heptane) to afford the title compound as a beige oil. Step 2: Preparation of 4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinic acid 0 HO /\ NN N N A mixture of methyl 4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinate and an aqueous solution 10 of sodium hydroxide ( 2.5N, 4.0 mL) in tetrahydrofuran (10 mL) was stirred for 2 hours at room temperature. Tetrahydrofuran was removed in vacuo and the aqueous residue was acidified to pH 6 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) followed by brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (1.05 g, 88%). LC/MS (5 15 100% CH 3
CN/H
2 0, 8 min) 4.03 min, m/z 262 (M+H). Step 3: Preparation of N-(4-fluoro-3-methylbenzvi)-4-(2-isobutvl-2H-tetrazol-5- v)-6-methylpicolinamide F 0 N / HN NN A mixture of 4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinic acid (0.050 g, 0.19 mmol) and 1 hydroxybenzatriazole (31 mg, 0.23 mmol) in tetrahydrofuran (5 mL) was stirred for 5 min. (4-Fluoro-3 20 methylphenyl)methanamine (27 mg, 0.19 mmol) and polymer supported carbodiimide (0.23 g, 0.29 mmol) were then added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (23 mg, 32%). 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 9.20 (t, J=6.6 Hz, 1 H), 8.41 (s, 1 H), 8.05 (s, 1 H), 7.23 (d, J=7.3 Hz, 1 H), 7.12 - 7.20 (m, 1 H), 6.93 - 7.10 (m, 1 H), 25 4.61 (d, J=6.6 Hz, 2 H), 4.46 (d, J=5.9 Hz, 2 H), 2.65 (s, 3 H), 2.27 - 2.40 (m, 1 H), 2.19 (s, 3 H), 0.92 (d, J=6.6 Hz, 6 H). Example 447 N-(4-Fluoro-3-methoxybenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinamide 434 WO 2009/016498 PCT/IB2008/002046 F 0 -O Nz7N N - N A mixture of 4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolinic acid (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)-6 methylpicolinamide, Example 446) (0.050 g, 0.19 mmol) and 1-hydroxybenzatriazole (31 mg, 0.23 5 mmol) in tetrahydrofuran ( 5 mL) was stirred for 5 minutes. 4-Fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2 ((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrimidine-4-carboxamide, Example 1) (31 mg, 0.19 mmol) and polymer supported carbodiimide (0.23 g, 0.29 mmol) were added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was concentrated and the 10 residue was purified by reverse phase preparative HPLC to afford the title compound (18 mg, 24%). H NMR (400 MHz, DMSO-d 6 ) 5 ppm 9.21 (t, J=6.22 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.05 - 7.21 (m, 2 H), 6.89 (d, J=2.9 Hz, 1 H), 4.61 (d, J=6.6 Hz, 2 H), 4.48 (d, J=5.9 Hz, 2 H), 3.80 (s, 3 H), 2.65 (s, 3 H), 2.19 - 2.40 (m, 1 H), 0.92 (d, J=7.3 Hz, 6 H). 15 Example 448 N-(3-Methoxybenzyl)-4-(2-isobutyl-2H-tetrazoI-5-yl)-6-methylpicolinamide N O -0 N
-
N N1 x The title compound was prepared in a similar manner to N-(3-methoxybenzyl)-6-methyl-4-(2 ((tetrahydrofuran-2-yl)methyl)-2H-tetrazol-5-yl)picolinamide (Example 425) by reaction with 2 20 methylpropan-1-ol and afforded 20.9 mg (34%) as a solid. LC/MS (5%-95% CH 3
CN/H
2 0, 4.5 min.; 95% CH 3 CN, 1.5 min.): 3.638 min., m/z 381 (M+H). Example 449 6-((4-(2-isobutyl-2H-tetrazol-5-yl)-2-methylpicolinamido)methyl)-1 H-indole-2-carboxamide N-N 0 H H2NN N H N H 0 435 WO 2009/016498 PCT/IB2008/002046 Step 1: Preparation of methyl 6-((4-(2-isobutyl-2H-tetrazol-5-yl)-2-methylpicolinamido)methyl)-1
H
indole-2-carboxylate N-N // \ N - N -O NN N H 0 A mixture of 4-(2-isobutyl-2H-tetrazol-5-yl)-6-methylpicolin ic acid (prepared as described in 5 step 2 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(2-isobutyl-2H-tetrazol-5-y)-6 methylpicolinamide, Example 446) (0.090 g, 0.34 mmol) and 1-hydroxybenzatriazole (56 mg, 0.41 mmol) in N,N-dimethylacetamide (3 mL) was stirred for 5 minutes. Methyl 6-(aminomethyl)-1H-indole 2-carboxylate (71 mg, 0.34 mmol) was then added followed by triethylamine (0.106 mL, 0.758 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.52 mmol). The mixture 10 was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (2 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica column chromatography (0-50% ethyl acetate/heptane) to afford the title compound (140 mg, 93%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.25 (t, J=6.22 Hz, 1 H), 8.52 (br. s., 15 2 H), 8.43 (s, 1 H), 8.06 (s, 1 H), 7.58 (d, J=8.78 Hz, 1 H), 7.41 (s, 1 H), 6.97 - 7.16 (m, 1 H), 4.62 (d, J=7.32 Hz, 4 H), 3.83 (s, 3 H), 2.65 (s, 3 H), 2.26 - 2.38 (m, 1 H), 0.92 (d, J=6.59 Hz, 6 H). Step 2: Preparation of methyl 6-((4-(2-isobutyl-2H-tetrazol-5-vl)-2-methylPicolinamido)methyl)- I H indole-2-carboxylate N-N // \
H
2 N N N & H 0 20 A solution of ammonia in methanol (7 N, 15 mL) was added to methyl 6-((4-(2-isobutyl-2H tetrazol-5-yl)-2-methylpicolinamido)methyl)-1H-indole-2-carboxylate (0.13 g, 0.29 mmol) and the mixture was heated to 60 *C in a sealed vial for 30 hours. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (15 mg, 10%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 11.40 (s, 1 H), 9.19 (t, J=6.59 Hz, 1 H), 8.42 (s, 1 H), 25 8.11 (s, 1 H), 8.06 (s, 1 H), 7.84 (br. s., 1 H), 7.52 (d, J=8.05 Hz, 1 H), 7.39 (s, 1 H), 7.23 (br. s., 1 H), 6.93 - 7.10 (m, 1 H), 4.61 (t, J=7.69 Hz, 4 H), 2.64 (s, 3 H), 2.22 - 2.42 (m, 1 H), 0.92 (d, J=6.59 Hz, 6 H). 436 WO 2009/016498 PCT/IB2008/002046 Example 450 N-(3-methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide 0< N /' N O N NH
NH
2 0 N 5 Step 1: Preparation of 6-methylpyridine-2,4-dicarboxylic acid 0 HO - OH N A solution of ammonia in ethanol (2 M, 400 mL) was cooled to 0 *C. Pyruvic acid (29.6 mL, 425 mmol) was added dropwise maintaining the temperature below 5 *C. After complete addition, the mixture was stirred for 30 min and then filtered. The resulting solid was washed with cold ethanol and 10 immediately transferred to a 2 L Erlenmeyer. The above procedures are repeated and the resulting solids were combined and dissolved in water (100 mL). The mixture was heated to reflux for 30 min and then diluted with 1 N hydrochloric acid (200 mL). The mixture was cooled in an ice bath and further acidified until acidic. The resulting precipitate was filtered and washed with ethyl ether to afford the title compound as a solid (10.97 g, 27%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 13.52 (br, 2 H), 15 8.20 (d, J=0.7 Hz, 1 H), 7.90 (d, J=1.0 Hz, 1 H), 2.62 (s, 3H). Step 2: Preparation of bis(perfluorophenyl) 6-methylpyridine-2,4-dicarboxylate F F F O F F F O\ F_ F F N / O F O F F 6-Methylpyridine-2,4-dicarboxylic acid (10.87 g, 60.0 mmol) and 1,3-dicyclohexylcarbodiimide (27.24 g, 132.0 mmol) were dissolved in N,N-dimethylformamide (400 mL). Pentafluorophenol (33.13 20 g, 180 mmol) was added in N,N-dimethylformamide (25 mL). The mixture was allowed to stir at room temperature for 18 hours and then the solvent was removed in vacuo. The residue was diluted with dioxane (500 mL) and filtered. The filtrate was concentrated, dissolved in dichloromethane/hexane (2/1, 100 mL), and filtered through a silica plug (5 cm x 8 cm) eluting with dichloromethane/hexane (2/1). The filtrate was concentrated, dissolved in ethyl acetate (500 mL), and washed with saturated 25 aqueous sodium bicarbonate (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica column chromatography (CH 2
CI
2 /hexane, 1/2; 1/1). After concentration, the residue was triturated with hexanes and filtered to afford the title compound as a solid (8.45 g, 27%). MS (ES+) m/z 514 (M+H). 437 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of N-(3-methoxybenzyl)-6-methylpyridin e-2.4-dicarboxamide 0 0 O N /
NH
2 | H N , A solution of bis(perfluorophenyl) 6-methylpyridine-2,4-dicarboxylate (4.23 g, 8.24 mmol) in dichloromethane (150 mL) was cooled to -78 *C. A solution of 3-methoxybenzylamine (1.24 g, 9.07 5 mmol) and diisopropylethylamine (1.12 mL, 9,07 mL) in dichloromethane (10 mL) was added. The mixture was allowed to slowly warm to room temperature over 20 hours. The solvent was removed in vacuo and the residue was dissolved in tetrahydrofuran (50 mL). A solution of ammonia (0.5 M in dioxane, 18.1 mL, 9.07 mmol) was added followed by diisopropylethylamine (1.12 mL, 9.07 mmol). The mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The 10 resulting residue was suspended in ethyl acetate and filtered to afford the title compound as a white solid (2.36 g, 96%). MS (ES+) m/z 300 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.16 (t, J=6.4 Hz, 1 H), 8.31 (s, 1 H), 8.22 (d, J=0.8 Hz, 1 H), 7.81 (d J=1.1 Hz, 1 H), 7.70 (s, 1 H), 7.20 (t, J=8.1 Hz, 1 H), 6.89-6.85 (m, 2 H), 6.78 (dd, J=8.2, 1.9 Hz, 1 H), 4.46 (d, J=6.4, 2 H), 3.69 (s, 3 H), 2.59 (s, 3 H). Step 4: Preparation of N-(3-methoxvbenzvl)-6-methVl-4-(1H-1,2,4-triazol-3-vl)picolinamide N / - N H I N 15 N-(3-Methoxybenzyl)-6-m ethylpyridine-2,4-dicarboxamide (599 mg, 2.0 mmol) and N,N dimethylformamide dimethylacetal (26.5 mL) was heated at 110 *C such that any methanol formed is collected through a short path condenser. After 2 h, the remaining ,N-dimethylformamide dimethylacetal was removed in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and 20 hydrazine hydrate (344 pL, 6.0 mmol) was added. The mixture was heated at 90 0C for 2 hours and then allowed to cool to room temperature. The reaction mixture was poured into water (20 mL), cooled in an ice bath, and adjusted to pH 7 with 2.5 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated. The residue was crystallized from ethyl 25 acetate/ether ether/hexane to afford the title compound as a white solid (486 mg, 75%). MS (APCI+) m/z 324 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 14.48 (s, 1 H), 9.19 (t, J=6.1 Hz, 1 H), 8.74 (s, 1 H), 8.44 (s, 1 H), 8.02 (s, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.94-6.89 (m, 2 H), 6.82 (dd, J=8.1, 1.9 Hz, 1 H), 4.50 (d, J=6.4 Hz, 2 H), 3.73 (s, 3 H), 2.64 (s, 3 H). 438 WO 2009/016498 PCT/IB2008/002046 Step 5: Preparation of tert-butyl (trans)-4-( 2-(-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl) I H-1,2,4-triazol-1 -yl)methvl)cvclohexvlcarbamate 0- N/0 NH N O / \ H 0 N N-(3-Methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (323 mg, 1.00 mmol), 5 polymer supported triphenylphosphine (698 mg, 1.50 mmol), and tert-butyl trans-(4 hydroxymethyl)cyclohexylcarbamate (275 mg, 1.20 mmol) were suspended in THF (16 mL). Di-tert butyl azodicarboxylate (345 mg, 1.50 mmol) was added. The mixture was allowed to warm to room temperature and stir for 18 hours. The reaction mixture was filtered and the resin washed with THF (20 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography 10 (CH 2
CI
2 /methanol, 100/1; 100/2; 100/4). Combined fractions were concentrated to afford the title compound as a foaming white solid (491 mg, 92%). MS (ES+) m/z 535 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.4 Hz, 1 H), 8.69 (s, 1 H), 8.39 (s, 1 H), 7.97 (d, J=1.1 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 - 6.89 (m, 2 H), 6.82 (dd, J=8.1, 1.9 Hz, 1 H), 6.70 (d, J=7.8 Hz, 1 H), 4.50 (d, J=6.4 Hz, 2 H), 4.12 (d, J=7.0 Hz, 2 H), 3.73 (s, 3 H), 3.21 - 3.11 (m, 1 H), 2.63 (s, 3 H), 1.82 - 1.71 15 (m, 3 H), 1.59 - 1.53 (m, 2 H), 1.36 (s, 9 H), 1.15 - 1.01 (m, 4 H). Step 6: Preparation of N-(3-methoxvbenzvl)-4-(1-(((trans)-4-aminocclohexyl)methyl)- 1H-1,2,4-triazol 3-yl)-6-methylpicolinamide O- N ~N NH NH 2 0 N tert-Butyl (trans)-4-((3-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-1H-1,2,4-triazol 20 1-yl)methyl)cyclohexylcarbamate (380 mg, 0.71 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.06 mL, 14.2 mmol) was added. The mixture was allowed to stand for 2 hours and was then concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with 1N NaOH solution (2 x 10 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a glass which slowly solidified (276 mg, 89%). MS (ES+) m/z 435 (M+H). 25 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.17 (t, J=6.4 Hz, 1 H), 8.68 (s, 1 H), 8.39 (d, J=0.9 Hz, 1 H), 7.97 (d, J=1.2 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.93 - 6.89 (m, 2 H), 6.82 (ddd, J=8.2, 2.5, 0.8 Hz, 1 H), 4.50 (d, J=6.4 Hz, 2 H), 4.11 (d, J=7.1 Hz, 2 H), 3.73 (s, 3 H), 2.63 (s, 3 H), 2.48 - 2.40 (m, 1 H), 1.84 - 1.71 (m, 3 H), 1.57 - 1.51 (m, 2 H), 1.40 (br. s., 1 H), 1.09 - 0.90 (m, 4 H). Example 451 30 N-(3-Methoxybenzyl)-6-methyl-4-(1-(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-1 H-1,2,4 triazol-3-yl)picolinamide 439 WO 2009/016498 PCT/IB2008/002046 0 N "; 0 NH N \\ H O 0 N N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide (prepared as described in Example 450) (135 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (86.6 pL, 0.62 mmol) and methanesulfonyl chloride (28.9 pL, 5 0.37 mmol) were added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated on to silica. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2; 100/4) to afford the title compound as a white solid (115 mg, 72%). MS (ES+) m/z 513 (M+H). IH NMR (400 10 MHz, DMSO-d 6 ) 6 ppm 9.17 (t, J=6.4 Hz, 1 H), 8.69 (s, 1 H), 8.39 (s, 1 H), 7.97 (d, J=1.1 Hz, I H), 7.24 (t, J=8.1 Hz, I H), 6.98 (d, J=7.4 Hz, 1 H), 6.93 - 6.89 (m, 2 H), 6.82 (dd, J=8.2, 1.7 Hz, 1 H), 4.50 (d, J=6.4 Hz, 2 H), 4.13 (d, J=7.0 Hz, 2 H), 3.73 (s, 3 H), 3.09 - 3.00 (m, 1 H), 2.88 (s, 3 H), 2.63 (s, 3 H), 1.90 (d, J=12.1 Hz, 2 H), 1.85 - 1.76 (m, 1 H), 1.59 (d, J=12.0 Hz, 2 H), 1.26 - 1.02 (m, 4 H). Example 452 15 N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-acetamidocyclohexyl)m ethyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide 'NH N N IP H O N N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)-6 methylpicolinamide (prepared as described in Example 450) (135 mg, 0.31 mmol) was dissolved in 20 dichloromethane (5 mL). Triethylamine (86.6 pL, 0.62 mmol), DMAP (7.6 mg, 0.062 mmol), and acetyl chloride (26.5 pL, 0.37 mmol) was added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated onto silica. The crude product was purified by silica column chromatography (CH 2
CI
2 /methanol, 100/1; 25 100/2; 100/4; 100/5) to afford the title compound as a white foaming solid (105 mg, 71%). MS (ES+) m/z 477 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.4 Hz, 1 H), 8.69 (s, 1 H), 8.40 (s, 1 H), 7.97 (s, 1 H), 7.69 (d, J=7.7 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.94 - 6.90 (m, 2 H), 6.82 (dd, J=8.1, 2.1 Hz, 1 H), 4.50 (d, J=6.3 Hz, 2 H), 4.13 (d, J=7.0 Hz, 2 H), 3.73 (s, 3 H), 3.46 (br. s., 1 H), 2.63 (s, 3 H), 1.88 - 1.72 (m, 6 H), 1.62 - 1.55 (m, 2 H), 1.15 - 1.02 (m, 4 H). 440 WO 2009/016498 PCT/IB2008/002046 Example 453 2-((trans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-1 H-1,2,4-triazol-1 yl)methyl)cyclohexylamino)-2-oxoethyl acetate 0-< N/' 0-" NH / N N O H 0 N O 5 N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)- 1 H- 1,2,4-triazol-3-yl)-6 methylpicolinamide (prepared as described in Example 450) (335 mg, 0.77 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (215pL, 1.54 mmol), DMAP (18.8 mg, 0.15 mmol), and acetoxyacetyl chloride (99.5 pL, 0.93 mmol) were added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (80 mL) and washed 10 with saturated aq. sodium bicarbonate solution (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2; 100/4). Fractions were concentrated, and upon addition of EtOAc, the product crystallized. The resulting slurry was filter to afford the title compound as a white crystalline solid (288 mg, 70%). MS (ES+) m/z 535 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 15 Hz, 1 H), 8.70 (s, 1 H), 8.40 (s, 1 H), 7.97 (d, J=1.1 Hz, 1 H), 7.85 (d, J=7.9 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.94 - 6.88 (m, 2 H), 6.82 (dd, J=8.1, 2.1 Hz, 1 H), 4.50 (d, J=6.4 Hz, 2 H), 4.38 (s, 2 H), 4.14 (d, J=7.0 Hz, 2 H), 3.73 (s, 3 H), 3.55 - 3.46 (m, 1 H), 2.63 (s, 3 H), 2.06 (s, 3 H), 1.89 - 1.73 (m, 3 H), 1.63 - 1.57 (m, 2 H), 1.24 - 1.04 (m, 4 H). Example 454 20 N-(3-Methoxybenzyl)-4-(1 -(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,4-triazol-3 yl)-6-methylpicolinamide NH N OH / \ H O N 2-((trans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 1 H-1,2,4-triazol- 1 yl)methyl)cyclohexylamino)-2-oxoethy acetate (prepared as described in Example 453) (200 mg, 25 0.375 mmol) was dissolved in THF (15 mL). Lithium hydroxide (26.9 mg, 1.12 mmol) followed by water (5.0 mL) were added. The mixture was stirred for 1 hour and then the THF was removed in vacuo. The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated to afford an oil. The residue was dissolved in ethyl acetate/methanol (4/1) and partially concentrated until solids formed. The suspension was 30 filtered to afford the title compound as a white solid (165 mg, 89%). MS (ES+) m/z 493 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.70 (s, I H), 8.40 (d, J=0.8 Hz, 1 H), 7.97 (d, J=1.2 Hz, 1 H), 7.44 (d, J=8.3 Hz, 1 H), 7.24 (t, J=8.1 Hz, 1 H), 6.89 - 6.93 (m, 2 H), 6.82 (dd, 441 WO 2009/016498 PCT/IB2008/002046 J=8.1, 1.8 Hz, 1 H), 5.39 (t, J=5.6 Hz, 1 H), 4.50 (d, J=6.3 Hz, 2 H), 4.14 (d, J=7.0 Hz, 2 H), 3.75 (d, J=5.6 Hz, 2 H), 3.73 (s, 3 H), 3.61 - 3.51 (m, 1 H), 2.63 (s, 3 H), 1.88 - 1.77 (m, 1 H), 1.74 (d, J=12.5 Hz, 2 H), 1.59 (d, J=12.5 Hz, 2 H), 1.27 (qd, J=12.4, 2.6 Hz, 2 H), 1.10 (qd, J=12.7, 2.4 Hz, 2 H). Example 455 5 N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide F O/ N 0- N N'KI NH NH 2 0 N Step 1: Preparation of N-(4-fluoro-3-methoxvbenzyl)-6-methylpyridine-2,4-dicarboxamide 0 0 N /' NH 2 H FN 10 A solution of bis(perfluorophenyl) 6-methylpyridine-2,4-dicarboxylate (prepared as described in step 2 of the synthesis of N-(3-methoxybenzyl)-4-(1-(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4 triazol-3-yl)-6-methylpicolinamide, Example 450) (104 g) in dichloromethane (945 mL) was cooled to 70 *C. A solution of 4-fluoro-3-methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of N-(4-fluoro-3-methoxybenzyl)-6-(2-((trans-4-aminocyclohexyl)methyl)-2H-tetrazol-5 15 yl)pyrimidine-4-carboxamide, Example 1) (23.5 g, 123 mmol) and triethylamine (33.4 mL, 240 mmol) in dichloromethane (140 mL) was added. The mixture was allowed to slowly warm to room temperature over 20 hours. The solvent was removed in vacuo and the residue was dissolved in tetrahydrofuran (575 mL). Triethylamine (18.4 mL, 132 mmol) was added followed by a solution of ammonia (0.5 M in dioxane, 260 mL, 130 mmol). The mixture was stirred at room temperature for 20 h, and then the 20 solvent was removed in vacuo. The resulting residue was suspended in ethyl acetate and filtered. The resulting solid was again suspended in methanol and filtered to afford the title compound as a white solid (27.7 g, 75%). MS (ES+) m/z 318 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.19 (t, J=6.4 Hz, 1 H), 8.32 (br. s., 1 H), 8.22 (d, J=0.8 Hz, 1 H), 7.81 (d, J=1.2 Hz, 1 H), 7.71 (br. s., 1 H), 7.14 (dd, J=8.5, 1.9 Hz, 1 H), 7.10 (dd, J=11.5, 8.3 Hz, 1 H), 6.82 - 6.87 (m, 1 H), 4.45 (d, J=6.4 Hz, 2 25 H), 3.78 (s, 3 H), 2.59 (s, 3 H). 442 WO 2009/016498 PCT/IB2008/002046 Step 2: Preparation of N-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-Vl)picolinamide N / N- NH F H N N-(4-Fluoro-3-methoxybenzyl)-6-methylpyridine-2,4-dicarboxamide (27.67 g, 87 mmol) and N,N-dimethylformamide dimethylacetal (290 mL) was heated at 110 *C such that any methanol formed 5 is collected through a short path condenser. After 2 h, the remaining ,N-dimethylformamide dimethylacetal was removed in vacuo. The residue was dissolved in glacial acetic acid (293 mL) and hydrazine hydrate (15.6 mL, 323 mmol) was added. The mixture was heated at 90 *C for 2 hours and then allowed to cool to room temperature. The reaction mixture was poured into water (250 mL) and filtered to afford the title compound as a solid (24.1 g, 81%). MS (ES+) m/z 342 (M+H). 'H NMR (400 10 MHz, DMSO-d 6 ) 6 ppm 14.47 (br. s., 1 H), 9.19 (t, J=6.4 Hz, 1 H), 8.67 (br. s., 1 H), 8.41 (s, 1 H), 7.98 (d, J=1.2 Hz, 1 H), 7.15 (dd, J=8.3, 1.9 Hz, 1 H), 7.11 (dd, J=11.7, 8.5 Hz, 1 H), 6.89 - 6.84 (m, 1 H), 4.46 (d, J=6.4 Hz, 2 H), 3.79 (s, 3 H), 2.60 (s, 3 H) Step 3: Preparation of tert-butyl (trans)-4-((3-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 methylpyridin-4-yl)-1H-1,2,4-triazol-1-yl)methyl)cyclohexylcarbamate F 0 N NN< 0 ~N ONH N O H 0 N 15 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (683 mg, 2.00 mmol), polymer supported triphenylphosphine (1.40 g, 3.00 mmol), and tert-butyl trans-(4 hydroxymethyl)cyclohexylcarbamate (550 mg, 2.40 mmol) were suspended in tetrahydrofuran (32 mL). Di-tert-butyl azodicarboxylate (691 mg, 3.00 mmol) was added. The mixture was allowed to warm to 20 room temperature and stir for 18 hours. The reaction mixture was filtered and the resin washed with tetrahydrofuran (40 mL). The filtrate was concentrated. The crude product was purified by silica column chromatography (CH 2
CI
2 /methanol, 100/1; 100/2; 100/4). Combined fractions were concentrated to afford the title compound as a foaming white solid (955 mg, 86%). MS (ES+) m/z 533 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.4 Hz, 1 H), 8.66 (s, 1 H), 8.36 (d, J=0.8 Hz, 1 25 H), 7.94 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (dd, J=11.7, 8.3 Hz, 1 H), 6.86 (ddd, J=8.3, 4.4, 1.9 Hz, 1 H), 6.67 (d, J=7.9 Hz, 1 H), 4.46 (d, J=6.4 Hz, 2 H), 4.09 (d, J=7.0 Hz, 2 H), 3.79 (s, 3 H), 3.12 (br. s., 1 H), 2.60 (s, 3 H), 1.74 (br. s., 3 H), 1.57 - 1.50 (m, 2 H), 1.33 (s, 9 H), 1.12 0.98 (m, 4 H). 443 WO 2009/016498 PCT/IB2008/002046 Step 4: Preparation of N-(4-fluoro-3-methoxybenzvl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)- 1 H 1,2,4-triazol-3-yl)-6-methylpicolinamide F \ N ' -N NH NH 2 0 N tert-Butyl (trans)-4-((3-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-1H 5 1,2,4-triazol-1 -yl)methyl)cyclohexylcarbamate (950 mg, 1.72 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2.55 mL, 34.4 mmol) was added. The mixture was allowed to stand for 2 hours and was then concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH solution (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a foaming solid (730 mg, 94%). MS (ES+) m/z 453 10 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.4 Hz, 1 H), 8.65 (s, 1 H), 8.36 (d, J=0.8 Hz, 1 H), 7.94 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.6, 2.0 Hz, 1 H), 7.11 (dd, J=11.7, 8.3 Hz, 1 H), 6.86 (ddd, J=8.3, 4.4, 2.0 Hz, 1 H), 4.46 (d, J=6.4 Hz, 2 H), 4.08 (d, J=7.0 Hz, 2 H), 3.79 (s, 3 H), 2.60 (s, 3 H), 2.44 - 2.38 (m, 1 H), 1.81 - 1.61 (m, 3 H), 1.55 - 1.34 (m, 4 H), 1.06 - 0.82 (m, 4 H). Example 456 15 N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1 -(((trans)-4-(methylsulfonamido)cyclohexyl)methyl) I H-1,2,4-triazol-3-yl)picolinamide F O- N ' NH N H O O N N-(4-Fluoro-3-methoxybenzyl)-4-(1-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl) 6-methylpicolinamide (prepared as described in Example 455) (725 mg, 1.6 mmol) was dissolved in 20 dichloromethane (30 mL). Triethylamine (447 pL, 3.2 mmol) and methanesulfonyl chloride (149 pL, 1.92 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (100 mL). The mixture was washed with saturated aq. sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate and concentrated onto silica. The crude product was purified by silica column chromatography (CH 2 Cl 2 /methanol, 100/1; 100/2; 25 100/4). Fractions were concentrated and the resulting oil crystallized from ethyl acetate to afford the title compound as a white solid (623 mg, 73%). MS (ES+) m/z 531 (M+H). 'H NMR (400 MHz, DMSO d 6 ) 6 ppm 9.18 (t, J=6.4 Hz, 1 H), 8.66 (s, 1 H), 8.36 (d, J=0.8 Hz, 1 H), 7.94 (d, J=1.1 Hz, 1 H), 7.15 (dd, J=8.5, 1.7 Hz, 1 H), 7.11 (dd, J=11.5, 8.3 Hz, 1 H), 6.95 (d, J=7.4 Hz, 1 H), 6.86 (ddd, J=8.4, 4.3, 1.9 Hz, 1 H), 4.46 (d, J=6.3 Hz, 2 H), 4.10 (d, J=6.8 Hz, 2 H), 3.79 (s, 3 H), 3.05 - 2.97 (m, 1 H), 2.85 444 WO 2009/016498 PCT/IB2008/002046 (s, 3 H), 2.60 (s, 3 H), 1.87 (d, J=10.5 Hz, 2 H), 1.82 - 1.71 (m, 1 H), 1.56 (d, J=12.4 Hz, 2 H), 1.22 1.00 (m, 4 H). Example 457 N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4-acetamidocyclohexyl)methyl)-1 H-1,2,4-triazol-3 5 yl)-6-methylpicolinamide F O0N N -~N N NH N H 0 N N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl) 6-methylpicolinamide (prepared as described in Example 455) (115 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (70.8 pL, 0.51 mmol), DMAP (6.2 mg, 0.051 mmol), and acetyl 10 chloride (21.7 pL, 0.31 mmol) was added. The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL). The mixture was washed with saturated aq. sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated on to silica. The crude product was purified by silica column chromatography (Biotage 40S,
CH
2
CI
2 /methanol, 100/2 x 0.75 L; 100/4 x 0.75 L; 100/5 x 0.75 L) to afford the title compound as a 15 white foaming solid (109 mg, 87%). MS (ES+) m/z 495 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.20 (t, J=6.4 Hz, 1 H), 8.69 (s, 1 H), 8.40 (s, 1 H), 7.97 (s, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.18 (dd, J=8.5, 1.7 Hz, 1 H), 7.17 - 7.11 (m, J=11.6, 8.3 Hz, 1 H), 6.89 (ddd, J=8.2, 4.3, 1.9 Hz, 1 H), 4.49 (d, J=6.3 Hz, 2 H), 4.13 (d, J=7.0 Hz, 2 H), 3.82 (s, 3 H), 3.45 (br. s., 1 H), 2.63 (s, 3 H), 1.88 - 1.73 (m, 6 H), 1.62 - 1.56 (m, 2 H), 1.17 - 1.02 (m, 4 H). 20 Example 458 2-((trans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-1 H-1,2,4-triazol 1-yl)methyl)cyclohexylamino)-2-oxoethy acetate F NH N N 0 \ H 0 N~ O N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl) 25 6-methylpicolinamide (prepared as described in Example 455) (349 mg, 0.77 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (215 pL, 1.54 mmol), DMAP (18.8 mg, 0.15 mmol), and acetoxyacetyl chloride (99.5 pL, 0.93 mmol) were added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (80 mL) and washed with saturated aq. sodium bicarbonate solution (2 x 20 mL). The organic layer was dried over sodium 445 WO 2009/016498 PCT/IB2008/002046 sulfate and concentrated. The crude product was purified by silica column chromatography
(CH
2 Cl 2 /methanol, 100/1; 100/2; 100/4). Fractions were concentrated, and upon addition of EtOAc, the product crystallized. The resulting slurry was filter to afford the title compound as a white solid (290 mg, 68%). MS (ES+) m/z 553 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.4 Hz, 1 H), 5 8.70 (s, 1 H), 8.40 (s, 1 H), 7.97 (s, 1 H), 7.85 (d, J=7.9 Hz, 1 H), 7.18 (dd, J=8.1, 1.7 Hz, 1 H), 7.14 (dd, J=11.5, 8.3 Hz, 1 H), 6.89 (ddd, J=8.1, 4.6, 1.9 Hz, 1 H), 4.49 (d, J=6.3 Hz, 2 H), 4.38 (s, 2 H), 4.14 (d, J=7.0 Hz, 2 H), 3.82 (s, 3 H), 3.55 - 3.46 (m, 1 H), 2.63 (s, 3 H), 2.06 (s, 3 H), 1.88 - 1,74 (m, 3 H), 1.63 - 1.56 (m, 2 H), 1.24 - 1.03 (m, 4 H). Example 459 10 N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H 1,2,4-triazol-3-yl)-6-methylpicolinamide F N NH N OH H 0 N 2-((trans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-y)-1 H-1,2,4 triazol-1-yl)methyl)cyclohexylamino)-2-oxoethy acetate (prepared as described in Example 458) (207 15 mg, 0.375 mmol) was dissolved in THF (15 mL). Lithium hydroxide (26.9 mg, 1.12 mmol) followed by water (5.0 mL) were added. The mixture was stirred for 1 hour and then the tetrahydrofuran was removed in vacuo. The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated to afford an oil. The residue was dissolved in acetonitrile and partially concentrated, and upon standing, the product 20 crystallizes. The slurry was filtered to afford 63 mg of a white solid, The filtrate was concentrated, dissolved in a minimum amount of acetonitrile, and seeded to afford a second crop of 79 mg. The two crops were combined to afford the title compound as a white solid (142 mg, 74%). MS (ES+) m/z 511 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.21 (t, J=6.4 Hz, 1 H), 8.70 (s, 1 H), 8.40 (s, 1 H), 7.97 (d, J=0.9 Hz, 1 H), 7.44 (d, J=8.3 Hz, 1 H), 7.18 (dd, J=8.5, 1.7 Hz, 1 H), 7.14 (dd, J=11.7, 8.3 Hz, 1 25 H), 6.89 (ddd, J=8.3, 4.5, 1.9 Hz, 1 H), 5.40 (t, J=5.7 Hz, 1 H), 4.49 (d, J=6.3 Hz, 2 H), 4.14 (d, J=7.0 Hz, 2 H), 3.82 (s, 3 H), 3.75 (d, J=5.6 Hz, 2 H), 3.60 - 3.52 (m, 1 H), 2.63 (s, 3 H), 1.88 - 1.77 (m, 1 H), 1.74 (d, J=10.1 Hz, 2 H), 1.59 (d, J=12.8 Hz, 2 H), 1.27 (dq, J=12.4, 2.3 Hz, 2 H), 1.10 (qd, J=12.5, 2.0 Hz, 2 H). Example 460 30 N-(4-Fluoro-3-methylbenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6 methylpicolinamide 446 WO 2009/016498 PCT/IB2008/002046 F N N NH NH 2 0 N Step 1: Preparation of N-(4-fluoro-3-methylbenzyl)-6-methylpyridine-2A-dicaboamide 0 0 F N NH 2 F A solution of bis(perfluorophenyl) 6-methylpyridine-2,4-dicarboxylate (prepared as described 5 in step 2 of the synthesis of N-(3-methoxybenzyl)-4-( -(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4 triazol-3-yl)-6-methylpicolinamide, Example 450) (104 g) in dichloromethane (945 mL) was cooled to 70 *C. A solution of 4-fluoro-3-methylbenzylamine (16.92 g, 122 mmol) and triethylamine (17.0 mL, 122 mmol) in dichloromethane (140 mL) was added. The mixture was allowed to slowly warm to room temperature over 20 hours. The solvent was removed in vacuo and the residue was dissolved in 10 tetrahydrofuran (575 mL). Triethylamine (19.2 mL, 138 mmol) was added followed by a solution of ammonia (0.5 M in dioxane, 271 mL, 135 mmol). The mixture was stirred at room temperature for 20 h, and then the solvent was removed in vacuo. The resulting residue was suspended in ethyl acetate and filtered to afford the title compound as a white solid (35.4 g, 62%). MS (ES+) m/z 302 (M+H). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.18 (t, J=6.3 Hz, 1 H), 8.32 (br. s., I H), 8.22 (d, J=0.9 Hz, 1 H), 15 7.81 (d, J=1.2 Hz, 1 H), 7.71 (br. s., 1 H), 7.20 (d, J=7.7 Hz, 1 H), 7.12 - 7.17 (m, 1 H), 7.04 (t, J=9.7 Hz, 1 H), 4.42 (d, J=6.4 Hz, 2 H), 2.58 (s, 3 H), 2.17 (d, J=1.6 Hz, 3 H). Step 2: Preparation of N-(4-fluoro-3-methylbenzyl)-6-methyl- 4 -(1H-1,24-triazol-3-vi)picolinamide N N -\ s- ,NH F H N I N-(4-Fluoro-3-methylbenzyl)-6-methylpyridine-2,4-dicarboxamide (35.0 g, 116 mmol) and N,N 20 dimethylformamide dimethylacetal (387 mL) was heated at 110 *C such that any methanol formed is collected through a short path condenser. After 2 h, the remaining ,N-dimethylformamide dimethylacetal was removed in vacuo. The residue was dissolved in glacial acetic acid (370 mL) and hydrazine hydrate (21.5 mL, 430 mmol) was added. The mixture was heated at 90 *C for 2 hours and then allowed to cool to room temperature. The reaction mixture was poured into water (375 mL) and 25 filtered to afford the title compound as a white solid (20.7 g, 55%). MS (ES+) m/z 326 (M+H). 447 WO 2009/016498 PCT/IB2008/002046 Step 3: Preparation of tert-butyl (trans)-4-((3-(2-((4-fluoro-3-methylbenzyl)carbamoy)-6-methylpyridin 4-vl)-1 H-1,2,4-triazol-1 -yl)methyl)cyclohexylcarbamate F N N ' ",0 NH / N N O 0 N N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (2.50 g, 7.68 5 mmol), tert-butyl trans-(4-hydroxymethyl)cyclohexyI carbamate (2.29 g, 10.0 mmol), and polymer supported-triphenylphosphine (5.12g, 11.5 mmol) were suspended in anhydrous tetrahydrofuran (100 mL). The mixture was cooled to 0 0C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (2.12 g, 9.22 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction was filtered and the filtrate was concentrated. The crude residue was 10 purified by silica gel column chromatography (50 g, 0-2% methanol/dichloromethane) to afford the title compound as a beige oil. Step 4: Preparation of N-(4-fluoro-3-methylbenzyl)-4-(1-(((trans)-4-aminocyclohexvl)methyl)-1 H-1,2,4 triazol-3-yl)-6-methylpicolin amide F \N' N N NH NH 2 O
N
0 N 15 tert-Butyl (trans)-4-((3-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-1H-1,2,4 triazol-1-yl)methyl)cyclohexylcarbamate was dissolved in dichloromethane (15 mL) and stirred with trifluoroacetic acid (4 mL) for 1 hour at room temperature. The reaction was concentrated and then triturated with diethyl ether to afford the title compound (2.76 g, 65%). LC/MS (5-95% CH 3
CN/H
2 0, 6 min) 3.99 min, m/z 437 (M+H). 20 Example 461 N-(4-Fluoro-3-methylbenzyl)-6-m ethyl-4-(1 (((trans)-4-(methylsufonamido)cyclohexyl)m ethyl) 1 H-1,2,4-triazol-3-yl)picolinamide 448 WO 2009/016498 PCT/IB2008/002046 F N NH N H O 0 N Triethylamine (0.11 mL, 0.77 mmol) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4 (1-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)-6-methylpicolinamide (prepared as described in Example 460) (96 mg, 0.22 mmol) in dichloromethane (2 mL). A solution of methane 5 sulfonyl chloride (30 mg) in dichloromethane (0.5 mL) was then added. The reaction mixture was stirred for 1 hour at room temperature and then was concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (17 mg, 15%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.01 - 9.20 (m, 1 H), 8.65 (s, 1 H), 8.37 (s, 1 H), 7.94 (br. s., 1 H), 6.99 - 7.30 (m, 3 H), 6.92 (d, J=7.3 Hz, 1 H), 4.45 (d, J=5.9 Hz, 2 H), 4.11 (d, J=7.3 Hz, 2 H), 10 3.03 (s, 1 H), 2.86 (s, 3 H), 2.60 (s, 3 H), 2.19 (s, 3 H), 1.88 (d, J=10.3 Hz, 2 H), 1.79 (s, 1 H), 1.58 (d, J=13.2 Hz, 2 H), 0.96 - 1.29 (m, 4 H). Example 462 N-(4-Fluoro-3-methylbenzyl)-4-(1 (((trans)-4-acetamidocyclohexyl) methyl)-1 H-1,2,4-triazol-3-yi) 6-methylpicolinamide F N N NH /N O N 15 Triethylamine (0.22 mL, 1.5 mmol) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4 (1 -(((trans)-4-aminocyclohexyl)methyl)- 1 H-1,2,4-triazol-3-yl)-6-methylpicolinamide (prepared as described in Example 460) (96 mg, 0.22 mmol) in dichloromethane (2 mL). A solution of acetyl chloride (21 mg) in dichloromethane (0.5 mL) was then added. The mixture was stirred for 1 hour at 20 room temperature and was then concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (18 mg, 17%). IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.13 (t, J=5.9 Hz, 1 H), 8.65 (s, 1 H), 8.37 (br. s., 1 H), 7.94 (s, 1 H), 7.63 (d, J=8.1 Hz, 1 H), 7.19 (dd, J=26.7, 6.2 Hz, 2 H), 6.92 - 7.11 (m, 1 H), 4.45 (d, J=5.9 Hz, 2 H), 4.11 (d, J=6.6 Hz, 2 H), 3.43 (br. s., 1 H), 2.60 (s, 3 H), 2.19 (s, 3 H), 1.69 - 1.88 (m, 5 H), 1.58 (br. s., 2 H), 0.95 25 1.20 (m, 5 H). Example 463 2-trans)-4-3-(2-(4-F uoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-1H-1,2,4-triazol-1 yl)methyl)cyclohexylamino)-2-oxoethyl acetate 449 WO 2009/016498 PCT/IB2008/002046 F NH N(N N O" N / H 0 N 0 Triethylamine (0.22 mL, 1.5 mmol) was added to a solution of N-(4-fluoro-3-methylbenzyl)-4 (1-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)-6-methylpicolinamide (prepared as described in Example 460) (96 mg, 0.22 mmol) in dichloromethane (2 mL). A solution of acetoxy acetyl 5 chloride (36 mg) in dichloromethane (0.5 mL) was added. The mixture was stirred for 1 hour at room temperature and was then concentrated. The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (26 mg). Example 464 N-(4-Fluoro-3-methylbenzyl)-4-(1 -(((trans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1,2,4 10 triazol-3-yl)-6-methylpicolinamidemide F N N NH NN OH \ H O N 2-((trans)-4-((3-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridin-4-y)-1 H-1,2,4-triazol 1-yl)methyl)cyclohexylamino)-2-oxoethy acetate (prepared as described in Example 464) (26 mg) was dissolved in acetonitrile (amount). A 2.5N sodium hydroxide solution (amount) was added and the 15 mixture was stirred for 2 hours. The mixture was acidified to ph 6-7 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to 18 mg of the title compound. 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.13 (t, J=6.2 Hz, 1 H), 8.66 (s, 1 H), 8.37 (br. s., 1 H), 7.94 (s, 1 H), 7.36 (d, J=8.8 Hz, 1 H), 6.94 - 7.26 (m, 3 H), 5.32 (d, J=5.1 Hz, 1 H), 4.45 (d, J=6.6 Hz, 2 H), 4.11 (d, J=7.3 Hz, 2 H), 3.73 (d, J=5.1 Hz, 3 H), 3.53 (d, J=8.8 Hz, 1 H), 2.60 (s, 3 H), 20 2.19 (s, 2 H), 1.81 (br. s., 1 H), 1.73 (d, J=11.0 Hz, 2 H), 1.58 (d, J=11.7 Hz, 2 H), 1.17 - 1.34 (m, 2 H), 0.99 - 1.17 (m, 2 H). Example 465 N-(3-Methoxybenzyl)-4-(I-(((trans)-4-(hydroxymethyl)cyclohexyl)methyl)-IH-1,2,4-triazol-3-y)-6 methylpicolinamide 450 WO 2009/016498 PCT/IB2008/002046 0- N /;-N N H N OH 0 N N-(3-Methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(-(((trans)-4-aminocyclohexyl)methyl)-1H-1,2,4 triazol-3-yl)-6-methylpicolinamide, Example 450) (0.20 g, 0.6 mmol), trans-1,4 5 cyclohexylenedimethanol (0.18 g, 1.24 mmol), and polymer supported-triphenylphosphine (0.72 g, 1.6 mmol) were suspended in anhydrous tetrahydrofuran (5 mL). The mixture was cooled to 0 *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (0.29 g, 1.2 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction was filtered and the filtrate was concentrated. The crude residue was purified by reverse phase preparative HPLC (5 10 95% gradient acetonitrile/water) to afford the title compound as a white solid (97 mg, 35%). 'H NMR (400 MHz, DMSO-d 6 ) J ppm 9.11 (t, J=6.2 Hz, 1 H), 8.65 (s, 1 H), 8.37 (s, 1 H), 7.94 (s, 1 H), 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.1 Hz, 1 H), 4.48 (d, J=5.9 Hz, 2 H), 4.24 - 4.32 (m, 1 H), 4.19 (d, J=5.9 Hz, 1 H), 4.01 - 4.15 (m, 2 H), 3.71 (s, 3 H), 2.60 (s, 3 H), 1.81 (dd, J=11.4, 4.0 Hz, 1 H), 1.71 (d, J=11.7 Hz, 2 H), 1.58 (d, J=13.2 Hz, 2 H), 1.20 - 1.35 (m, 1 H), 0.91 - 1.06 (m, 2 H), 0.74 15 0.91 (m, 2 H). Example 466 rac-N-(3-Methoxybenzyl)-4-(1-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1 H-1,2,4 triazol-3-yl)-6-methylpicolinamide -N '' OD .' H ONN NH -_ OH O N 20 N-(3-Methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (prepared as described in step 4 of the synthesis of N-(3-methoxybenzyl)-4-(1 -(((trans)-4-aminocyclohexyl)methyl)-1 H-1,2,4 triazol-3-yl)-6-methylpicolinamide, Example 450) (32 mg, 0.10 mmol), trans-2,5-bis-(hydroxymethyl) 1,4-dioxane (prepared as described in step 3 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2 (((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4 25 carboxamide, Example 61) ( 22 mg, 0.15 mmol), and polymer supported-triphenylphosphine (0.071 g, 0.15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL). The mixture was cooled to 0 *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (28 mg, 0.12 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction was filtered and the filtrate was concentrated. The crude residue was purified by reverse phase preparative 30 HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (15 mg, 33%). 'H NMR (400 MHz, DMSO-d) 6 ppm 9.12 (t, J=6.2 Hz, 1 H), 8.63 (s, 1 H), 8.37 (s, 1 H), 7.95 (s, 1 H), 451 WO 2009/016498 PCT/IB2008/002046 7.22 (t, J=8.1 Hz, 1 H), 6.90 (br. s., 2 H), 6.80 (d, J=8.8 Hz, 1 H), 4.60 - 4.70 (m, 1 H), 4.48 (d, J=6.6 Hz, 2 H), 4.18 - 4.39 (m, 5 H), 3.88 (d, J=9.5 Hz, 2 H), 3.78 (d, J=1 1.0 Hz, 1 H), 3.71 (s, 3 H), 2.56 2.71 (m, 4 H), 1.32 - 1.44 (m, 1 H). Example 467 5 rac-N-(4-Fluoro-3-methoxybenzyl)-4-(1-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl) 1 H-1,2,4-triazol-3-yl)-6-methylpicolinamide F S'(0 O NH _ OH 0 N N-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (prepared as described in step 1 of the preparation of N-(4-fluoro-3-methoxybenzyl)-4-(1 -(((trans)-4 10 aminocyclohexyl)methyl)-1 H-1,2,4-triazol-3-yl)-6-methylpicolinamide, Example 455) (34 mg, 0.10 mmol), trans-2,5-bis-(hydroxymethyl)-1,4-dioxane (prepared as described in step 3 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide, Example 61) (22 mg, 0.15 mmol), and polymer supported triphenylphosphine (0.071 g, 0.15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL). The 15 mixture was cooled to O *C in an ice bath for 15 min then di-tert-butyl azodicarboxylate (28 mg, 0.12 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction was filtered and the filtrate was concentrated. The crude residue was purified by reverse phase preparative HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (22 mg, 47%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.14 (t, J=6.6 Hz, 1 H), 8.63 (s, 1 H), 20 8.37 (s, 1 H), 7.95 (s, 1 H), 7.05 - 7.22 (m, 2 H), 6.88 (br. s., 1 H), 4.64 (t, J=5.1 Hz, 1 H), 4.47 (d, J=6.6 Hz, 2 H), 4.18 - 4.40 (m, 5 H), 3.88 (d, J=9.5 Hz, 2 H), 3.67 - 3.83 (m, 5 H), 2.61 (s, 3 H), 1.30 1.45 (m, 1 H). Example 468 rac-N-(4-Fluoro-3-methylbenzyl)-4-(1-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-1
H
25 1,2,4-triazol-3-yl)-6-methylpicolinamide F N N ',0 - ~N NH _ O OH 0 N N-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1H-1,2,4-triazol-3-yl)picolinamide (prepared as described in step 2 of the synthesis of N-(4-fluoro-3-methylbenzyl)-4-(1-(((trans)-4 aminocyclohexyl)methyl)-1H-1,2,4-triazol-3-yl)-6-methylpicolinamide, Example 460) (33 mg, 0.10 452 WO 2009/016498 PCT/IB2008/002046 mmol), trans-2,5-bis-(hydroxymethyl)-1,4-dioxane (prepared as described in step 3 of the synthesis of rac-N-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl) 2-methylpyrimidine-4-carboxamide, Example 61) (22 mg, 0.15 mmol), and polymer supported triphenylphosphine (0.071 g, 0.15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL). The 5 mixture was cooled to O *C in an ice bath for 15 min and then di-tert-butyl azodicarboxylate (28 mg, 0.12 mmol) was added. The reaction was allowed to warm to room temperature while stirring over 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude residue was purified by reverse phase preparative HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (20 mg, 44%). 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 9.13 (t, J=6.2 Hz, 1 10 H), 8.63 (s, 1 H), 8.37 (s, 1 H), 7.94 (s, 1 H), 7.19 (dd, J=27.1, 6.6 Hz, 2 H), 7.04 (t, J=9.2 Hz, 1 H), 4.64 (t, J=5.1 Hz, 1 H), 4.45 (d, J=6.6 Hz, 2 H), 4.18 - 4.40 (m, 5 H), 3.88 (d, J=9.5 Hz, 2 H), 3.78 (d, J=1 1.7 Hz, 2 H), 2.60 (s, 3 H), 2.19 (s, 3 H), 1.37 (br. s., 1 H). In Vitro MMP Inhibition Analysis Matrix Metalloproteinase inhibitor compounds were analyzed in in vitro MMP Inhibition assays 15 to determine their ability to inhibit the MMP cleavage of peptide substrates. Inhibition constants (Ki) were calculated from the assayed compound-MMP interactions. Human recombinant MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15 were used in these assays. The enzymes are prepared following known laboratory procedures. Protocols for the preparation and use of these enzymes are available in the scientific 20 literature. See, for example, Frije et al., J. Biol. Chem., 269(24), 16766-73 (1994). In addition, many MMPs may be purchased from suppliers. For example, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-24, MMP-25, and MMP-26 are commercially available from R&D Systems in their 2006 catalog. Available in the 2006 Millipore Chemicon catalog are MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP 25 9, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17 and MMP-24. The MMP-1 proenzyme may be purified from spent media of MMP-1-transfected HT-1080 cells and the protein purified on a zinc chelating column. The MMP-2 proenzyme may be purified by gelatin Sepharose chromatography from MMP-2-transfected p2AHT2 cells. The MMP-9 proenzyme may be purified by gelatin Sepharose chromatography from spent media of MMP-9-transfected 30 HT1080 cells. The catalytic domain MMP-3 cDNA may be used to express the catalytic domain enzyme in E. coli inclusion bodies. Then the enzyme is solubilized in urea, purified on a preparative C-14 reverse phase HPLC column, and refolded in the presence of zinc acetate and purified for use. The MMP-7 cDNA may be used to express the enzyme in E. coli inclusion bodies. Then the 35 enzyme is solubilized in urea, purified on a preparative C-14 reverse phase HPLC column, and refolded in the presence of zinc acetate and purified for use. The MMP-13 may be obtained as a proenzyme from a full-length cDNA clone using baculovirus expression. The expressed proenzyme was first purified over a heparin agarose column, 453 WO 2009/016498 PCT/IB2008/002046 and then over a chelating zinc chloride column. Further details on baculovirus expression systems may be found in, for example, Luckow et al., J. Virol., 67, 4566-79 (1993). The MMP-14 cDNA may be used to express the catalytic domain enzyme in E. coli inclusion bodies. Then the enzyme is solubilized in urea, purified on a preparative C-14 reverse phase HPLC 5 column, and refolded in the presence of zinc acetate and purified for use. The catalytic domain of MMP-12 and MMP-15 enzymes were purchased commercially for these assays. All full length MMPs were activated using 4-aminophenylmercuric acetate ("APMA", Sigma Chemical, St. Louis, Mo.) or trypsin. MMP-9 also was activated using human recombinant MMP-3 10 following standard cloning and purification techniques. The fluorogenic, methoxycoumarin-containing polypeptide substrate MCA ArgProLeuGlyLeuDpaAlaArgGluArgNH2 was used as the MMP substrate in the MMP inhibition assays for human recombinant MMP-1, MMP-2, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15. Here, "MCA" is 7-methoxycoumarin-4-yl acetyl and "Dpa" is 3-(2,4-dinitrophenyl)-L-2,3-di 15 aminopropionyl group. In the absence of MMP inhibitory activity, the substrate is cleaved at the Gly Leu peptide bond. The cleavage separates the highly fluorogenic peptide from the 2,4-dinitrophenyl quencher, resulting in an increase of fluorescent intensity. For the human MMP-1, MMP-2, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15 assays, dilutions of the inhibitors (or salts thereof) were prepared in 100% dimethyl sulfoxide (DMSO). 20 The stock solutions were diluted in Buffer A (100 mM Tris-HCI, 100 mM NaCl, 10 mM CaCl 2 , 0.005% polyoxyethylene 23 lauryl ether, pH 7.5) to obtain solutions with different compound concentrations, i.e., assay solutions with different concentrations of the assayed MMP inhibitory compound in 1% DMSO. The experiment controls contained the same amount of Buffer A /DMSO as the assayed sample, but contained no inhibitor. 25 The fluorogenic, methoxycoumarin-containing polypeptide substrate Mca-Arg-Pro-Lys-Pro Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2 (Bachem catalog number M-21 10) was used as the MMP substrate in the MMP inhibition assays for catalytic domain of human recombinant MMP-3 (which refers to the catalytic domain of stromelysin). Here, "MCA" is 7-methoxycoumarin-4-yl acetyl and "Dpa" is 3-(2,4-dinitrophenyl)-L-2,3-di- aminopropionyl group. In the absence of MMP inhibitory 30 activity, the substrate is cleaved at the Gly-Leu peptide bond. The cleavage separates the highly fluorogenic peptide from the 2,4-dinitrophenyl quencher, resulting in an increase of fluorescent intensity. For the human MMP-3 assay, dilutions of the inhibitors (or salts thereof) were prepared in 100% DMSO. The stock solutions were diluted in Buffer B (50 mM N-morpholinoethane sulfonate 35 ("MES"), 100 mM NaCl, 10 mM CaCl 2 , 0.005% polyoxyethylene 23 lauryl ether, pH 6.0) ) to obtain solutions with different compound concentrations, i.e., assay solutions with different concentrations of the assayed MMP inhibitory compound in 1% DMSO. The experiment controls contained the same amount of Buffer B /DMSO as the assayed sample, but contained no inhibitor. To determine Kj, the inhibitor samples are incubated at room temperature for 1 hr in the 40 presence of enzyme and then 4 puM of appropriate MMP substrate was added, and samples were 454 WO 2009/016498 PCT/IB2008/002046 analyzed on a Tecan SpectraFlour Plus plate reader. The excitation wavelength is 330 nm, and the emission (fluorescence) wavelength is 420 nm. In the absence of MMP inhibitory activity, the substrate is cleaved at the Gly-Leu bond resulting in an increase of relative fluorescence. Inhibition is observed as a reduced rate of increase in relative fluorescence. 5 The inhibitors are analyzed using a single low enzyme concentration with a single substrate concentration fixed at or below the Km. This protocol is a modification of method by Knight et al., FEBS Lett., 296(3), 263-266 (1992). Apparent inhibitory constants are determined by non-linear regression of reaction velocity as a function of inhibitor and enzyme concentration using Morrison's equation, as described by Kuzmic, Anal. Biochem. 286, 45-50 (2000). Modifications were made in the non-linear 10 regression method to allow a common control reaction rate and effective enzyme concentration to be shared between all dose-response relationships on a given assay plate. Since the substrate concentration was chosen to be at or below the Km, the apparent K's from this analysis were reported as K's without correction for the influence of substrate. 15 Example hMMP K, (nW) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 1 NT 2 >10000 8.91 3 NT 4 34.5 5 NT 6 >10000 >10000 7870 >10000 >10000 >10000 0.41 >10000 >10000 7 >10000 0.96 8 >10000 0.98 9 NT 10 3260 >10000 0.13 11 >10000 >10000 8960 >10000 >10000 >10000 0.63 >10000 >10000 12 >10000 >10000 2.97 >10000 >10000 13 NT 14 >10000 6.76 15 >10000 2.4 16 11 17 >10000 2.21 18 >10000 1.15 19 >10000 1.67 20 NT 21 2620 0.09 22 NT 455 WO 2009/016498 PCT/IB2008/002046 Example hMMP K, (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 23 >10000 5030 3500 >10000 >10000 >10000 0.08 >10000 >10000 24 5520 1.37 25 >10000 >10000 2170 >10000 >10000 >10000 0.77 >10000 >10000 26 >10000 >10000 9470 >10000 >10000 >10000 6.87 >10000 >10000 27 7030 2.23 28 >10000 >10000 9340 >10000 >10000 >10000 0.81 >10000 >10000 29 9070 1.1 30 >10000 2.15 31 NT 32 >10000 2.85 33 >10000 2.54 34 >10000 5.68 35 >10000 2 36 >10000 2.78 37 >10000 5.91 38 NT 39 >10000 >10000 >10000 >10000 >10000 >10000 6.05 >10000 >10000 40 >10000 >10000 8880 >10000 >10000 >10000 0.69 >10000 >10000 41 NT 42 >10000 >10000 8910 >10000 >10000 >10000 4.97 >10000 >10000 43 5130 0.58 44 NT 45 >10000 >10000 >10000 >10000 >10000 >10000 2.69 >10000 >10000 46 >10000 3.12 47 NT 48 8460 1.7 49 NT 50 >10000 2.91 51 >10000 6.94 52 >10000 3.26 53 >10000 7.08 54 >10000 >10000 8410 >10000 >10000 >10000 6.17 >10000 >10000 55 27.4 56 22.5 57 >10000 6.85 58 >10000 >10000 >10000 >10000 >10000 >10000 3.94 >10000 >10000 456 WO 2009/016498 PCT/IB2008/002046 Example hMMP KI (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 59 8.85 60 16.9 61 >10000 >10000 >10000 >10000 >10000 >10000 5.84 >10000 >10000 62 >10000 >10000 >10000 >10000 >10000 >10000 3.67 >10000 >10000 63 >10000 >10000 >10000 >10000 >10000 >10000 7.81 >10000 >10000 64 >10000 >10000 >10000 >10000 >10000 >10000 3 >10000 >10000 65 9990 6290 >10000 6290 9380 4240 1.58 >10000 >10000 66 >10000 >10000 >10000 >10000 >10000 >10000 4.19 >10000 >10000 67 >10000 6.39 68 >10000 >10000 9940 >10000 >10000 >10000 3.46 >10000 >10000 69 6670 7.65 70 9.6 71 >10000 1.69 72 >10000 >10000 8290 >10000 >10000 >10000 1.75 >10000 >10000 73 >10000 >10000 >10000 >10000 >10000 >10000 4.12 >10000 >10000 74 32.8 75 10.5 76 21.6 77 18.4 78 >10000 4-77 79 5230 4380 >10000 >10000 5790 4550 6.5 >10000 >10000 80 >10000 2.34 81 >10000 25.9 82 22.5 83 16.2 84 16.1 85 NT 86 >10000 >10000 >10000 >10000 >10000 >10000 0.51 >10000 >10000 87 NT 88 >10000 >10000 >10000 >10000 >10000 >10000 0.2 >10000 >10000 89 >10000 0.29 90 3.11 91 >10000 3.65 92 NT 93 >10000 1.09 94 NT 457 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 95 >10000 >10000 >10000 >10000 >10000 >10000 0.16 >10000 >10000 96 NT 97 >10000 5.94 98 >10000 1.36 99 >10000 >10000 9970 >10000 >10000 >10000 1.67 >10000 >10000 100 >10000 4.01 101 >10000 3.66 102 9890 4.26 103 >10000 3.73 104 >10000 >10000 >10000 >10000 >10000 >10000 2.86 >10000 >10000 105 >10000 7.86 106 >10000 1.8 107 >10000 6.6 108 >10000 2.85 109 26.9 110 NT 111 >10000 3820 3.01 >10000 >10000 112 >10000 2 113 NT 114 >10000 7640 2.66 >10000 >10000 115 >10000 >10000 10.8 116 NT 117 6330 1080 0.63 >10000 >10000 118 >10000 >10000 >10000 >10000 >10000 3900 2.94 >10000 >10000 119 6860 2140 2.23 120 >10000 4.6 121 6.51 122 NT 123 >10000 >10000 >10000 >10000 >10000 >10000 3.01 >10000 >10000 124 >10000 5 125 21 126 5340 3910 >10000 >10000 6270 3360 27.1 >10000 >10000 127 16.2 128 >10000 >10000 >10000 >10000 >10000 >10000 6.81 >10000 >10000 129 121 130 NT 458 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 131 123 132 40.2 133 26.2 134 NT 135 >10000 >10000 >10000 >10000 >10000 >10000 1.88 >10000 >10000 136 >10000 >10000 >10000 >10000 >10000 >10000 3.37 >10000 >10000 137 NT 138 46.6 139 41.2 140 21.7 141 NT 142 17.8 143 18.5 144 22.8 145 >10000 12.1 146 >10000 31.4 147 NT 148 >10000 15.9 149 >10000 >10000 >10000 >10000 >10000 >10000 6.47 >10000 >10000 150 >10000 27.4 151 >10000 11.1 152 10400 4710 1590 >10000 >10000 6060 1.37 >10000 >10000 153 >10000 >10000 >10000 >10000 >10000 >10000 15.6 >10000 >10000 154 >10000 >10000 >10000 >10000 >10000 >10000 0.25 >10000 >10000 155 >10000 0.45 156 >10000 0.50 157 >10000 1.03 158 >10000 1.98 159 3.57 160 1.33 161 >10000 >10000 >10000 >10000 >10000 >10000 2.27 >10000 >10000 162 >10000 0.68 163 >10000 2.26 164 >10000 10 165 >10000 4.54 166 >10000 2.68 459 WO 2009/016498 PCT/IB2008/002046 Example hMMP K; (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 167 >10000 >10000 >10000 >10000 >10000 >10000 3.64 >10000 >10000 168 9030 1.4 169 >10000 2.99 170 NT 171 >10000 >10000 >10000 >10000 >10000 >10000 0.66 >10000 >10000 172 >10000 1.23 173 >10000 0.59 174 >10000 0.88 175 >10000 0.39 176 0.54 177 >10000 0.74 178 >10000 1.18 179 25.3 180 >10000 0.59 181 >10000 1.5 182 >10000 >10000 0.17 183 >10000 4.19 184 >10000 >10000 >10000 >10000 >10000 >10000 3.18 >10000 >10000 185 NT 186 >10000 0.57 187 >10000 2.67 188 >10000 17.8 189 9420 4.21 190 1.32 191 >10000 2.3 192 >10000 4.01 193 >10000 3.26 194 NT 195 >10000 0.87 196 >10000 4.69 197 23.8 198 8.46 199 2.69 200 7.6 201 10.6 202 7.57 460 WO 2009/016498 PCT/IB2008/002046 Example hMMP K, (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 203 >10000 4.07 204 >10000 7.53 205 >10000 17.8 206 >10000 9.63 207 >10000 8.82 208 >10000 4.15 209 NT 210 5.31 211 >10000 1.36 212 7.06 213 >10000 1.96 214 2.98 215 >10000 >10000 >10000 >10000 >10000 >10000 1.55 >10000 >10000 216 >10000 2.66 217 8.48 218 6.34 219 NT 220 8300 2.9 221 4420 0.49 222 6220 0.57 223 NT 224 7.92 225 >10000 >10000 >10000 >10000 >10000 >10000 3.71 >10000 >10000 226 13.6 227 >10000 3.16 228 7.01 229 4.7 230 >10000 5 231 32.3 232 >10000 3.06 233 NT 234 NT 235 >10000 1.74 236 8.18 237 8360 1.08 238 9.16 461 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 239 >10000 3.8 240 8.67 241 NT 242 24.8 243 5.03 244 24.5 245 19.9 246 21 247 35.7 248 14.8 249 NT 250 >10000 9.58 251 8.48 252 >10000 7.47 253 >10000 >10000 >10000 >10000 >10000 >10000 3.76 >10000 >10000 254 9.88 255 NT 256 >10000 >10000 >10000 >10000 >10000 >10000 4.39 >10000 >10000 257 9.51 258 >10000 37.2 259 NT 260 2.5 261 5.06 262 1.54 263 NT 264 0.56 265 53.8 266 >10000 7.54 267 0.75 268 11000 0.16 269 2.21 270 >10000 4.19 271 1.8 272 2.35 273 2.71 274 0.78 462 WO 2009/016498 PCT/IB2008/002046 Example hMMP K; (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 275 >10000 1.8 276 1.8 277 >10000 1.85 278 NT 279 >10000 >10000 7210 >10000 >10000 >10000 2.66 >10000 >10000 280 7130 0.97 281 NT 282 3.53 283 >10000 14.2 284 8.79 285 0.24 286 1.76 287 >10000 >10000 6340 >10000 >10000 >10000 4.06 >10000 >10000 288 NT 289 >10000 1.17 290 13.6 291 22.5 292 6.74 293 4.34 294 NT 295 NT 296 >10000 2.79 297 0.92 298 0.30 299 6750 0.67 300 3850 0.90 301 15.6 302 0.28 303 >10000 1.69 304 >10000 4.62 305 7.62 306 0.62 307 4.05 308 23.8 309 46.7 310 38.5 463 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 311 47.2 312 19.5 313 17.1 314 3.19 315 29.3 316 3.78 317 6.31 318 8260 14.7 319 5970 7.3 320 18.8 321 19.6 322 10100 2.06 323 6630 1.18 324 15.4 325 >10000 7.47 326 15.6 327 9.19 328 15.9 329 32.9 330 8730 4.1 331 >10000 2.99 332 4340 1.87 333 >10000 >10000 >10000 >10000 >10000 >10000 4.46 >10000 >10000 334 >10000 10-9 335 14.5 336 9.84 337 6.94 338 10.5 339 12.9 340 8.08 341 33.3 342 >10000 3.54 343 >10000 5.2 344 >10000 >10000 >10000 >10000 >10000 >10000 4.02 >10000 >10000 345 >10000 >10000 >10000 >10000 >10000 >10000 3.25 >10000 >10000 346 >10000 2.69 464 WO 2009/016498 PCT/IB2008/002046 Example hMMP K, (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 347 >10000 3.61 348 >10000 1.35 349 5630 0.27 350 >10000 4.3 351 2.95 352 3.46 353 0.53 354 3.99 355 >10000 7.24 356 17.3 357 >10000 2.65 358 682 359 >10000 4.47 360 18 361 288 362 42.5 363 28.9 364 274 365 8620 1.59 366 7.9 367 199 368 17.6 369 11 370 260 371 20.1 372 63.5 373 NT 374 56 375 46.4 376 17.3 377 >10000 4 378 >10000 5.18 379 NT 380 11.1 381 >10000 37.6 382 >10000 29.5 465 WO 2009/016498 PCT/IB2008/002046 Example hMMP KI (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 383 >10000 >10000 >10000 >10000 >10000 >10000 16.6 >10000 >10000 384 5.77 385 18.3 386 17.3 387 100 388 >10000 8.85 389 171 390 >10000 14.2 391 47.8 392 >10000 >10000 >10000 >10000 >10000 >10000 4.3 >10000 >10000 393 NT 394 >10000 >10000 >10000 >10000 >10000 >10000 4.47 >10000 >10000 395 NT 396 >10000 3.86 397 6800 0.88 398 NT 399 >10000 17.9 400 >10000 2.56 401 >10000 10.3 402 >10000 14.7 403 >10000 >10000 >10000 >10000 >10000 >10000 11.7 >10000 >10000 404 >10000 >10000 14.9 >10000 >10000 405 >10000 >10000 11.2 >10000 >10000 406 NT 407 >10000 0.83 408 21.7 409 >10000 5.06 410 >10000 12.3 411 >10000 10.6 412 >10000 >10000 >10000 >10000 >10000 >10000 7.58 >10000 >10000 413 NT 414 >10000 >10000 >10000 >10000 >10000 >10000 0.43 >10000 >10000 415 15.2 416 >10000 2.52 417 >10000 5.82 418 9780 2.27 466 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 419 >10000 3.1 420 NT 421 >10000 2.23 422 NT 423 >10000 3.34 424 14.8 425 61.8 426 >10000 11.8 427 NT 428 7.65 429 20.6 430 >10000 8.58 431 15.4 432 11.8 433 16.5 434 10.9 435 >10000 5.02 436 25 437 2960 2.63 438 10.6 439 3460 0.57 440 4480 0.13 441 8170 1.69 442 3580 2.57 443 >10000 15.7 444 25 445 46.7 446 >10000 19.8 447 >10000 6.9 448 30.6 449 >10000 >10000 >10000 >10000 >10000 >10000 13 >10000 >10000 450 NT 451 >10000 8500 2.32 452 >10000 >10000 5.6 453 >10000 1.62 454 >10000 >10000 >10000 >10000 >10000 >10000 3.15 >10000 >10000 467 WO 2009/016498 PCT/IB2008/002046 Example hMMP Ki (nM) No. 01/FL 02/FL 03/CD 07/CD 09/FL 12/CD 13/FL 14/CD 15/CD 455 NT 456 5780 2550 0.62 457 >10000 4850 1.66 458 9740 0.81 459 >10000 >10000 >10000 >10000 >10000 7200 2.02 >10000 >10000 460 NT 461 7240 4.62 462 7.18 463 NT 464 14.6 465 >10000 >10000 8130 >10000 >10000 >10000 5.13 >10000 >10000 466 66.9 467 39.2 468 63.6 Cartilage damage in vitro assay Human articular cartilage (HAC) was dissected from knees obtained from Asterand from patients undergoing knee replacement. Apparently normal (not fibrillated) cartilage was cut in small 5 pieces (- 2 mm) and cultured in 96 well plates with 200 pla of DMEM media (Gibco BRL high glucose, 25 mM Hepes, containing 2 mM L-glutamine and 1 mM Sodium Pyruvate) freshly supplemented with 1x HL-1 (Bio Whitaker) and 5 pg/ml ascorbic acid (Sigma), and with or without 0.1 ng/ml IL-1f (R &D Systems, Minneapolis, MN) + 50 pg/ml Oncostatin M (R & D Systems). Some cartilage wells were incubated in the presence of serially diluted MMP inhibitors, tested in quadruplicate at 6 10 concentrations. Media were replaced every 3 to 5 days and cartilage was cultured for a total of 18-22 days. Conditioned media were frozen and analyzed later for hydroxyproline content (or type 11 collagen degradation biomarker TIINE). TIINE sandwich immunoassay for culture media. A chemiluminescent sandwich immunoassay was developed with the neoepitope 9A4 15 antibody (recognizing the conserved sequence at the C-terminus of the % type || collagen fragment GPPGPQG following collagenase cleavage) and the capture 5109 antibody (recognizing the type il collagen specific epitope GEPGDDGPS) as detailed elsewhere (Nemirovskiy et al., Anal. Biochem. 2007;361(1):93-101) utilizing the proprietary, chemiluminescent Bioveris technology (Bioveris Corporation, Gaithersburg, MD). This immunoassay utilizes a sandwich format on a paramagnetic 20 bead support phase in which the sandwich complex is bound to the bead in suspension, passed through a flow cell, and captured by a magnet. The process effectively separates the analyte from the 468 WO 2009/016498 PCT/IB2008/002046 sample, decreasing background interference and eliminating wash steps required in other formats. Briefly, serially diluted culture supernatant samples were assayed in a 96-well plate. In this one step assay, 25 pL of sample, 25 pL of streptavidin beads (0.4 mglmL), 25 pL of each antibody at 1pg/mL (Biotin conjugated mouse 5109 anti-capture and BVTAG labeled 9A4 anti-neoepitope) and 100pL of 5 assay buffer (DPBS, 0.1% BSA, 0.05% Tween 20, pH 7.4) were incubated for 2 hours at room temperature before reading on the Bioveris M384 Analyzer. Values were calculated from a standard curve prepared from either human 45-mer or bovine 30-mer (0.14-100 ng/ml) neoepitope peptide. Cartilage damage and/or joint degeneration in vivo assay: surgical-induce medial meniscus tear rat OA model 10 Adult male Sprague Dawley rats (Charles River, Wilmington, MA) weighing 275-300 g were allowed to acclimate for 1 week prior to surgery. OA was surgically induced as described (Bendele, "Animal models of osteoarthritis," J. Musculoskelet. Neuronal. Interact. 1 (2001) (4), pp. 363-376). Briefly, animals were anesthetized with isoflurane and the right knee joint prepped for surgery. The medial collateral ligament (MCL) was exposed by blunt dissection and transected to reflect the 15 meniscus toward the femur. The joint space was visualized and the meniscus was cut through the full thickness at its narrowest point to simulate a complete tear. The skin was closed with stainless steel staples. Compound or vehicle treatment started the day of surgery and continued for 3 to 4 weeks. The animals are then sacrificed, the femoro-tibial joint space lavaged with 1 00ul sterile saline to collect synovial fluid, and the total joint removed and fixed in 10% formalin for histology. Scoring was 20 performed by hispopathology quantification. 469

Claims (72)

1. A compound of Formula I 0 W, L 'G HAi M ,,Q Y I wherein 5 G is (C 13 alkylenyl)-Ra or Ra, wherein said C3 alkylenyl may be substituted by one or more substituents selected from OH and F; R' is Coe alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C1.6 alkyl may be substituted by one or more substituents selected from F, -OR3, -SR3, -C(=O)NR3R 3 5 , -NRR 35 , -NR3C(=O)R 35 , or -NR3SO 2 R 36 , and wherein said 10 heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R 2 , R , R4, R5, R10, R", and R2; M is N or C-Rb; Q is N or C-Rc, provided that if Q is C-Rc, then M is N; W is phenyl-(CI-e alkylenyl), pyridyl-(C 1 - 6 alkylenyl), or 9-membered heteroaryl-(C 1 - alkylenyl), 15 wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R and R3; Y is C-6 alkyl, C1re haloalkyl; or C1r hydroxyalkyl; L is 5-membered heteroaryl; R2 is H, F, CN, -OR', R , -C(=0)R', -NRR 3, -NR 8 C(=0)R 9 , -NR 8 SO 2 R , or -SO2RI; 20 R3 is H, F, CN, or -OR2; R4 is H, -(C1 alkylene)Rr, -C(=O)R , or -SO 2 R2; R5 is H or -(C1 alkyl), wherein said Cs- alkyl may be substituted by one or more R26 substituents; OR23 R is H, CN, -OR 3 , -SO 2 R , -NR 24C(0)R , -NR 24SO 2 R , or N-N 25 R' is -(C1 alkyl), -(C1.4 haloalkyl), -(C1 alkylene)OH, -NRaR 39, -NHSO 2 CH 3 , or -OR2; R is -(C1.4 alkylene)R 2, -NHR 24, or -OR 2 ; R'0 is H, F, CN, R , or -C(=O)R 7 ; R1 is H, F, CN, -OR , R' 2 , -C(=0)R', -NR 8 R 3 , -NR 8 C(=0)R', -NR'SO 2 R , or -SO 2 R2; R 12 is -(C1 alkyl), wherein said C1.4 alkyl may be substituted by one or more substituents 30 selected from CN, -OR 23 , -SR 3 , -SO 2 R , -NRR 3, -NR 24 C(=O)R 23 , and -NR 24SO 2 R , provided that any one carbon atom of said C1 alkyl is not substituted by more than one CN or more than one -OR2; R', R', R', R0, R 22 , R 24 , R 25 , R 33 , R , and R3 are independently H or -(C1.4 alkyl); R is H, F, or R 1 2 ; 35 R 2 is H, -(Cj4 alkyl), or -(C4 alkylene)OH; 470 WO 2009/016498 PCT/IB2008/002046 R 2 6 is H, OH, halo, NH 2 , or SH; R 2 is H, NH2, or -OR 2 9 ; R 29 is H, (C-6 alkyl), or -C(=O)(C-6 alkyl); R30 is H or F; 313 25 32 5 R is F, Cl, Br, -CN, -C(=O)NH 2 , -OH, -OR 32 , -OCH 2 CH 2 OR , R , ,or (C1 alkyl) optionally substituted by -OR or -OCH 2 CH 2 OR25 where R and R when adjacent may be taken together to constitute a group of the formula O-(CH 2 )n- or -O-(CH2)n-O-; n is 1 or 2; 10 R 32 is -(C1 alkyl) optionally substituted with one, two, or three F; R 3 6 is -(C1 alkyl) or -(C3-6 cycloalkyl); and R 37 is -(C1 alkyl), -(C3-6 cycloalkyl), or -(C1.4 alkylene)OH; R 3 and R are independently H, -(C1 alkyl), or R and R taken together form a 5- or 6 membered heterocycloalkyl; 15 or a pharmaceutically-acceptable salt thereof.
2. A compound according to claim 1 wherein Ra is Coe alkyl, 1,4-dioxanyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidinyl, cyclopentyl, 7-oxa-bicyclo[2.2.1]heptanyl, piperazinyl, 1,1'-dioxothiomorpholinyl, tetrahydro-1,1' 20 dioxothiopyranyl, tetrahydrothiopyranyl, piperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or oxazolidinonyl, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR3R 3 , -NR3R 3 5 , -NR3C(=O)R 35 , or -NR'SO 2 R 35 , and wherein said 1,4 dioxyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidinyl, cyclopentyl, 7-oxa-bicyclo[2.2.1]heptanyl, piperazinyl, 1,1'-dioxothiomorpholinyl, 25 tetrahydro-1,1'-dioxothiopyranyl, tetrahydrothiopyranyl, piperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or 2 3 4 5 10 11 oxazolidinonyl may be substituted by one or more substituents selected from R , R , RI, R , R10, R 21 and R
3. A compound according to claim 1 wherein Ra is CIe alkyl, 1,4-dioxanyl substituted by 10 2 2 3 30 R4 and R , piperidinyl substituted by R 2 and R 3 or by R 4 , cyclohexyl substituted by R and R or by R 4 , morpholinyl substituted by R 4 , thiomorpholinyl substituted by R 1 0 and R 2 , tetrahydropyranyl 10 21 2 3 substituted by R 3 and R" or by R'" and R , tetrahydropyranonyl, pyrrolidinyl substituted by R and R or by R 4 , cyclopentyl substituted by R 2 and R 3 , 7-oxa-bicyclo[2.2.1]heptanyl, piperazinyl substituted by R 4 and R 5 , 1,1'-dioxothiomorpholinyl, tetrahydro-1,1'-dioxothiopyranyl, tetrahydrothiopyranyl, 35 piperidinonyl substituted by R 5 , tetrahydrofuryl substituted by R 3 and R", pyrrolidinonyl substituted by R 5 , oxazolidinonyl substituted by R , wherein said alkyl may be substituted by one or more substituents selected from -ORM, -SR3, -C(=O)NRR 35 , -NR3R 3 5 , -NR3C(=O)R 35 , or -NR 34 S0 2 R 3 .
4. A compound according to claim 3 wherein Ra is C1 alkyl, 471 WO 2009/016498 PCT/IB2008/002046 0 R 3 3 3 X N RO 0 2R 4 N R 4 R R21 0 X Q RX 4 RO RO R 2 1 R 2 R 3 R 2 3 N-4 A/ R5 0 S N N-R 0 R 4 0" R 3 NR N-Rs N-R 5 O , or 0 , wherein said alkyl may be substituted by one or more 5 substituents selected from -OR3, -SR3, -C(=O)NR34R 35 , -NR34R 35 , -NR3C(=0)R 3 5 , or -NR 34 S0 2 R 3 5 ; and X is N or CH, provided that when X is N, G is (C2-3 alkylenyl)-Ra, wherein said C1.3 alkylenyl may be substituted by one or more substituents selected from OH and F. 10 5. A compound according to claim 4 wherein Ra is C1.6 alkyl, /0 /0 A R21 R 3 R 3 RIO R 2 R 4 RI 1 R 2 R 3 , or AXQ R2 R, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=0)NR3Ras, -NR3Ras, -NR3C(=O)R 35 , or -NR3S0 2 R 35 . 15 6. A compound according to claim 5 wherein Ra is C1.6 alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR34R 35 , -NR3Ras, -NR3C(=O)R 3 5 , or -NR3SO 2 R 35 .
7. A compound according to claim 6 wherein Ra is C1. alkyl, wherein said alkyl may be 20 substituted by one or more -OR3. 472 WO 2009/016498 PCT/IB2008/002046
8. A compound according to claim 5 wherein Ra is /021 3 R 0 R 0 R2 R4 R" R 2 R 3 ,or X R2 R 3 5 9. A compound according to claim 8 wherein Ra is /00 0 4 R21 R3 NR3 R - , 2 , R4 ,R , R2 R3,o 3 R2 o
10. A compound according to claim 1 wherein: 10 G is -CH 2 R, -CH 2 CH 2 Ra, -CH(Ra)CH 3 , -CH 2 CH 2 CH 2 Ra, -CH 2 CH(CH 3 )Ra -CH(Ra)CH 2 CH 3 , or Ra, wherein said CH, CH 2 , and CH 3 groups may be substituted by one or more substituents selected from OH and F; Ra is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, 15 piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR3, -SR 3 4 , -C(=O0)NR'R 35 , 20 -NR 34 R 3 , -NR 34 C(=0)R 35 , or -NR 34 S0 2 R 3 6 , and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R 2 , R 3 , R 4 , R , R'", R", and R 2 1 ; 25 W is phenyl-(C- 6 alkylenyl), pyridyl-(C- 6 alkylenyl), or indolyl-(C- 6 alkylenyl), wherein said C1. 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 3 1 ; 473 WO 2009/016498 PCT/IB2008/002046 Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; L is triazolyl, tetrazolyl, or oxadiazolyl; 5 R 4 is H, -(Cle alkylene)R, -C(=O)R , or -SO 2 R 2 , wherein said C 1 e alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1 -butylene, 2-butylene, 2,2-dimethylethylene, 1 -pentylene, 2 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 31 ; R 5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 10 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more R substituents; R 7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, -NHR 24 , or -OR 2, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 15 2-buty), 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; R 9 is -(C,. alkylene)R 2 1, -NHR 24 , or -OR 2 5 ; R 12 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-buty), 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R 12 may be substituted by one or more substituents selected 20 from CN, -OR , -SO 2 R , -NR8R3, -NR 24C(=0)R2, and -NR 24SO 2 R 23, provided that any one carbon atom of R 1 2 is not substituted by more than one CN or more than one -OR 23 ; R, Rc, R, R20, R22, R2 4 , R 2 5 , R 33 , R34, and R are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; R 23 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 25 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; R 2 6 is H, OH, F, Cl, Br, NH 2 , or SH; R 29 is H, -C(=0)CH 3 , -C(=O)CH 2 CH3, -C(=O)(CH 2 ) 2 CH 3 , -C(=O)CH(CH 3 ) 2 , -C(=O)(CH 2 ) 3 CH 3 , -C(=O)CH(CH 3 )CH 2 CH3, -C(=O)CH 2 CH(CH 3 ) 2 , -C(=O)(CH 2 ) 4 CH 3 , 30 -C(=0)CH 2 CH(CH 3 )CH 2 CH 3 , -C(=O)CH 2 C(CH 3 ) 3 , or -C(=0)(CH 2 )CH 3 ; R 31 is Cl, Br, -OR , methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2 CH 2 OR 25 ; R 32 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R may be substituted with one, two, or three F; 35 R 36 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl; and R 3 7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; 40 or a pharmaceutically-acceptable salt thereof. 474 WO 2009/016498 PCT/IB2008/002046
11. A compound according to claim 1 having Formula 1l: 0 W, L ,G HI N N Y ll. 5 12. A compound according to claim 11 having Formula IIA: 0 W, L Ra H N N Y 11A.
13. A compound according to claim 12 wherein L is triazolyl, tetrazolyl, or oxadiazolyl. 10 14. A compound according to claim 13 wherein L is H N- N-1 N-1 ,H ,or
15. A compound according to claim 14 wherein L is N -Ns N N N.- N N/ N 15 N ,or
16. A compound according to claim 14 of Formula IIA-1 0 N -N, Ra N N H I N N Y IIA-1. 20 17. A compound according to claim 14 of Formula IIA-2 475 WO 2009/016498 PCT/IB2008/002046 o N \ Ra W N N, -- N N Y IIA-2.
18. A compound according to claim 14 of Formula IIA-3 o N-:--N\ Ra N N - N N Y lA-3. 5
19. A compound according to claim 14 of Formula IIA-4 o N- 0 Ra N N H I N N Y IIA-4.
20. A compound according to any one of claims 13 through 19 wherein Ra is Coe alkyl, 0 R21 R3 N 3-O 10 R10 R2 , R4 , R4 R" R21 O R3 0 ,R R 10 R 21 R 2 R 3 R2 R 5 N N R 5 0 N N 4 0 R 4 0 R 3 NR 4 N-R 5 N-R 5 0 , or 0 , wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=0)NRNR 3 5 , -NR'Ras, -NR'C(=0)R 35 , or -NR S0 2 R 3 . 476 WO 2009/016498 PCT/IB2008/002046
21. A compound according to claim 20 wherein Ra is C 1 e alkyl, R21 R 3 R 3 S R0, R2, R4 ,R R 2 R 3 ,or R 3 R2 , Iwherein said alkyl may be substituted by one or more substituents selected 5 from -ORM, -SR3, -C(=O)NR3R , -NR3R 3 5 , -NR34C(=0)R", or -NR S0 2 R .
22. A compound according to claim 20 wherein Ra is CIe alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR3R 35 , -NR3R , -NR3C(=O)R , or -NR SO 2 Ras 10
23. A compound according to claim 22 wherein Ra is C 1 e alkyl, wherein said alkyl may be substituted by one or more -OR3.
24. A compound according to claim 21 wherein Ra is 0 4/0 R21 R3 NR3 150 0 ,R2 , 4 ,R" R2 R3 ,o 3 R2 R
25. A compound according to any one of claims 15 through 19 wherein: Ra is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 20 2,2-dimethylpropyl, 1-hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected 25 from -OR3, -SR3, -C(=O)NR4R 3 , -NR 34 R 35 , -NR 3 4 C(=O)R 35 , or -NR 34 S0 2 R 3 1, and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, 477 WO 2009/016498 PCT/IB2008/002046 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R 2 , R 3 , R 4 , R5, R10, R " , and R 21 ; W is phenyl-(CI- alkylenyl), pyridyl-(C- 6 alkylenyl), or indolyl-(C-e alkylenyl), wherein said C1. 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 5 dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 3 '; Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; 10 L is triazolyl, tetrazolyl, or oxadiazolyl; R is H, -(C1 alkylene)R 6 , -C(=O)R 9 , or -SO 2 R , wherein said Coe alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dimethylethylene, 1-pentylene, 2 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 3 ; 15 R 5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more R substituents; R 7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 20 2,2-dimethylpropyl, 1-hexyl, -NHR 24 , or -OR 2 , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; R9 is -(C1.4 alkylene)R 2 8 , -NHR 24, or -OR2; R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 25 2,2-dimethylpropyl, or 1-hexyl, wherein R2 may be substituted by one or more substituents selected from CN, -OR 23 , -S0 2 R 37 , -NRR 33 , -NR 2 4 C( =O)R 23 , and -NR 24 S0 2 R 23 , provided that any one carbon atom of R 12 is not substituted by more than one CN or more than one -OR 2 3 ; Rb, RC, R 8 , R 0, R 2 2 , R 24 , R 25 , R 3 1, R 3 4 , and R 3 are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; 30 R is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; R is H, OH, F, Cl, Br, NH 2 , or SH; R is H, -C(=O)CH3, -C(=O)CH 2 CH 3 , -C(=O)(CH 2 ) 2 CH 3 , -C(=O)CH(CH 3 ) 2 , 35 -C(=O)(CH 2 ) 3 CH 3 , -C(=0)CH(CH 3 )CH 2 CH 3 , -C(=O)CH 2 CH(CH 3 ) 2 , -C(=O)(CH 2 ) 4 CH 3 , -C(=0)CH 2 CH(CH 3 )CH 2 CH 3 , -C(=0)CH 2 C(CH 3 ) 3 , or -C(=0)(CH 2 )CH 3 ; R is Cl, Br, -OR , methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2 CH 2 OR 2 s; R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 40 2,2-dimethylpropyl, or 1-hexyl, wherein R may be substituted with one, two, or three F; 478 WO 2009/016498 PCT/IB2008/002046 R 3 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl; and R 37 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 5 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; or a pharmaceutically-acceptable salt thereof.
26. A compound according to any one of claims 11 through 25 wherein Y is methyl. 10 27. A compound according to any one of claims 11 through 26 wherein W is phenyl-(C- 6 alkylenyl), wherein said phenyl is substituted by one or more groups selected from R 3 0 and R 3 '.
28. A compound according to claim 27 wherein W is phenylmethyl, wherein said phenyl is substituted by one or more groups selected from R 30 and R. 15
29. A compound having the structure: F -O H 3C O NsN, N N N N N N HIH Y~ 0 OH 3 OH
30. A compound having the structure: F H3C' 0 N rN N N 'N N N 0 20 CH 3 OH
31. A compound having the structure: 479 WO 2009/016498 PCT/IB2008/002046 F H 3 C'O 0 N:N /N N N HI0 N N 50 CH 3
32. A compound having the structure: H 3 C-O O N N NN N N N y~ 0 5 CH 3 OH
33. A compound having the structure: H 3 C o N N N N H I0 N N CH 3 OH 10
34. A compound having the structure: H 3 C-O 0 NaNN N N N N N0 HI3 OH 3 -OH 480 WO 2009/016498 PCT/IB2008/002046
35. A compound having the structure: F 0 NN:::N /N N N N HI N N 0 CH 3 5 36. A compound having the structure: F H 3 C 0 0 N-:-.N -N N N N 0 N N 0 CH 3
37. A compound having the structure: H 3 C O N N0 N N~ N- N N O N CH 3 10
38. A compound having the structure: N N N OH NH -\/N 0 N
39. A compound having the structure: 481 WO 2009/016498 PCT/IB2008/002046 F ON N OrH 0N
40. A compound according to claim 1 having Formula IlIl: 0 W, N L ,G H Rb N Y ll. 5
41. A compound according to claim 40 having Formula lIlA: 0 W' N L Ra HI Rb Y lIlA.
42. A compound according to claim 41 wherein L is triazolyl, tetrazolyl, or oxadiazolyl. 10
43. A compound according to claim 42 wherein L is H NiNN - N NN N - N \KN N N N or
44. A compound according to claim 43 wherein L is WN N H RH N Rb 8lilA-1. 482 WO 2009/016498 PCT/IB2008/002046
46. A compound according to claim 41 of Formula 1lIA-2 o N \ Ra W ,N N R N R b Y IIIA-2. 5 47. A compound according to claim 41 of Formula IlA-3 o N:::N Ra W, N N'1;z -- N HKN Rb N Yl1A-3.
48. A compound according to claim 41 of Formula IlA-4 o N- 0 Ra W/ N N H Rb N Y111A-4. 10
49. A compound according to any one of claims 42 through 48 wherein Ra is Ce alkyl, O 00 R 21 R 3 N 3 RI /- R R4 , 'R4 R" R21 OR 0 ,RI RIO R 21 R 2 R 3 R2R R5 N/ N NR R4 ROR 4 0 R 3 483 WO 2009/016498 PCT/IB2008/002046 N-R 5 N-R 5 0 , or 0 , wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR", -C(=O)NR3R 3 5 , -NR 34 R 3 5 , -NR34C(=0)R 35 , or -NR 34 SO 2 R 35 .
50. A compound according to claim 49 wherein Ra is C1. alkyl, /0 / / R 21 R 3 N R 3 5 R 10 , R 2 , R 4 ,R1 R 2 R 3 ,or R3 R2 , Iwherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR R 35 , -NR Ras, -NR'C(=0)Ras, or -NR S0 2 Ra.
51. A compound according to claim 49 wherein Ra is C,.e alkyl, wherein said alkyl may be 10 substituted by one or more substituents selected from -OR', -SR', -C(=O)NR34R 3 , -NR3R 3 5 , -NR'C(=O)R 3 5 , or -NR 34 SO 2 R 35 .
52. A compound according to claim 51 wherein R' is C1.6 alkyl, wherein said alkyl may be substituted by one or more -OR34; 15 53. A compound according to claim 50 wherein Ra is /0 // )/0 / R21 /,a R3 N a R3 0 0 R 2 R 4 R 11 R 2 R 3 , or R 3 R2R
54. A compound according to any one of claims 44 through 48 wherein: 20 Ra is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 25 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected 484 WO 2009/016498 PCT/IB2008/002046 from -OR3, -SR 3 4 , -C(=O)NR 34 R", -NR34R 35, -NR 3 4 C(=O)R 35 , or -NR34SO 2 R 36, and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, 5 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R 2, R , R 4, R , R10, R", and R2; W is phenyl-(CI- 6 alkylenyl), pyridyl-(C 1 -e alkylenyl), or indolyl-(C- 6 alkylenyl), wherein said C1, 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said 10 phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 30 and R 3 '; Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; L is triazolyl, tetrazolyl, or oxadiazolyl; 15 R 4 is H, -(C1. alkylene)R 6 , -C(=O)R 9 , or -S0 2 R , wherein said CI- alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dimethylethylene, 1-pentylene, 2 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 30 and R 31 R 5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 20 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more R 2 substituents; R 7 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, -NHR 24 , or -OR 25 , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 25 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; R9 is -(C1 alkylene)R 2, -NHR 24, or -OR2s R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R2 may be substituted by one or more substituents selected 30 from CN, -OR 23 , -S0 2 R 3 , -NR 8 R 3 , -NR 24 C(=O)R 23 , and -NR 24 SO 2 R 23 provided that any one carbon atom of R 12 is not substituted by more than one CN or more than one -OR 23 ; R bR , RS, R 2 0, R2, R 24 , R 25 , R 33 , R 3 4 , and R 35 are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; R is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 35 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; R is H, OH, F, Cl, Br, NH 2 , or SH; R29 is H, -C(=O)CH3, -C(=O)CH 2 CH3, -C(=O)(CH 2 ) 2 CH 3 , -C(=O)CH(CH 3 ) 2 , -C(=O)(CH 2 ) 3 CH 3 , -C(=O)CH(CH 3 )CH 2 CH3, -C(=O)CH 2 CH(CH 3 ) 2 , -C(=O)(CH 2 ) 4 CH 3 , 40 -C(=0)CH 2 CH(CH 3 )CH 2 CH 3 , -C(=0)CH 2 C(CH3)3, or -C(=O)(CH 2 ) 5 CH 3 ; 485 WO 2009/016498 PCT/IB2008/002046 R 31 is Cl, Br, -OR , methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2 CH 2 OR2; R 32 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein R 3 2 may be substituted with one, two, or three F; 5 R 36 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl; and R 37 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; 10 or a pharmaceutically-acceptable salt thereof.
55. A compound according to any one of claims 40 through 54 wherein Y is methyl.
56. A compound according to claim 1 having Formula IV: 0 N G H I N / Rc 15 Y IV.
57. A compound according to claim 56 having Formula IVA: 0 W'N L Ra H I N / RC Y IVA. 20 58. A compound according to claim 57 wherein L is triazolyl, tetrazolyl, or oxadiazolyl.
59. A compound according to claim 58 wherein L is H N- NN-1 No N~N N' N\ N N N I\IIN o r 25 60. A compound according to claim 59 wherein L is N NsN - N N N N N 'O N N - N ,or\
61. A compound according to claim 59 of Formula IVA-1 486 WO 2009/016498 PCT/IB2008/002046 o N-:-N\ W' N N, N-R\a H N N / RC Y IVA-1.
62. A compound according to claim 59 of Formula IVA-2 O N -- ~\ W' N N/ N--Ra H N N Rc Y IVA-2. 5
63. A compound according to claim 59 of Formula IVA-3 O N-N WNN Ra H I N / Rc Y IVA-3.
64. A compound according to claim 59 of Formula IVA-4 O N-O N N H N /Rc 10 Y IVA-4.
65. A compound according to any one of claims 58 through 64 wherein Ra is C 1 .- alkyl, R21 R 3 N R 3 R - R2 , R4 ,R4,R R21 O0R3 0 R 10 R 21 R 2 R 3 R 2 R 487 WO 2009/016498 PCT/IB2008/002046 R5 N 0 0 ROO0 R " R 3 N R 4 N-R 5 R' 0 or 0 wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=O)NR34Rs, -NR'R 3 5 , -NR'C(=O)Ras, or -NR S0 2 R 35 . 5 66. A compound according to claim 65 wherein Ra is C1.e alkyl, / 0 R R N R3 R1 R 3 R 3 R R 3 ,or R 3 R2 R, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR", -C(=O)NR R 35 , -NR3Ras, -NR3C(=O)R 35 , or -NR3SO 2 R 35 . 10 67. A compound according to claim 65 wherein Ra is C 1 .6 alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR3, -SR3, -C(=0)NR R 35 , -NR3Ras, -NR3C(=O)R 35 , or -NR3SO 2 R 35 .
68. A compound according to claim 67 wherein Ra is C1.6 alkyl, wherein said alkyl may be 15 substituted by one or more -OR3;
69. A compound according to claim 66 wherein Ra is R21 R3 R3 R 0 2 , R4 ,R , R2 R3,o R3 R2R 20 70. A compound according to claim 69 wherein Ra is 488 WO 2009/016498 PCT/IB2008/002046 / _a/ /"C R 2R 0 R 1 0 R 2 R 1 , or R2 is CH(CH 3 )OH, C(CH 3 ) 2 0H, -NR C(=O)(C 1 .- alkylene)R 2, or -NR'SO 2 R36 R' 0 is CH(CH 3 )OH, or C(CH 3 ) 2 0H; and 5 R" is CH(CH 3 )OH, C(CH 3 ) 2 0H, -NRC(=0)(C 1 .- alkylene)R 2, or -NR'SO 2 R".
71. A compound according to any one of claims 60 through 64 wherein: Ra is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, 10 piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR3, -SR 34 , -C(=O)NR'Ras 15 -NR R", -NR 34 C(=O)R", or -NR'SO 2 R 3, and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R2, R3, R4, R5, R10, R", and R 21 ; 20 W is phenyl-(C-e alkylenyl), pyridyl-(C- 6 alkylenyl), or indolyl-(C- 6 alkylenyl), wherein said C 1 . 6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2 dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R 3 0 and R 31 ; Y is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2 25 dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br; L is triazolyl, tetrazolyl, or oxadiazolyl; R 4 is H, -(C1.6 alkylene)R , -C(=O)R 9 , or -S0 2 R , wherein said C 1 .6 alkylene is methylene, ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dimethylethylene, 1-pentylene, 2 30 pentylene, 2,2-dimethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R and R3; R5 is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, may be substituted by one or more 35 R substituents; R' is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, -NHR 2 4 , or -OR 2 5 , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 489 WO 2009/016498 PCT/IB2008/002046 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br; R9 is -(C1.6 alkylene)R 2, -NHR 4, or -OR"; R' 2 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 5 2,2-dimethylpropyl, or 1-hexyl, wherein R 1 2 may be substituted by one or more substituents selected from CN, -OR 23 , -S0 2 R 3 7 , -NR 8 R 33 , -NR 24 C(=0)R 23 , and -NR 24 S0 2 R 23 , provided that any one carbon atom of R is not substituted by more than one CN or more than one -OR2; Rb, RC, R 8, R 20 , R2, R 24 , R 2 5 , R 33 , R 34 , and R 3 5 are independently H, methyl, ethyl, 1-propyl, 2 propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl,; 10 R is H, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; R is H, OH, F, Cl, Br, NH 2 , or SH; R is H, -C(=0)CH 3 , -C(=O)CH 2 CH 3 , -C(=O)(CH 2 ) 2 CH 3 , -C(=O)CH(CH 3 ) 2 , 15 -C(=O)(CH 2 ) 3 CH 3 , -C(=O)CH(CH 3 )CH 2 CH 3 , -C(=O)CH 2 CH(CH 3 ) 2 , -C(=O)(CH 2 ) 4 CH 3 , -C(=O)CH 2 CH(CH 3 )CH 2 CH 3 , -C(=0)CH 2 C(CH 3 ) 3 , or -C(=O)(CH 2 ) 5 CH 3 ; R is Cl, Br, -OR 32 , methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1 pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, or -OCH 2 CH 2 OR2; R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 20 2,2-dimethylpropyl, or 1-hexyl, wherein R 3 2 may be substituted with one, two, or three F; R is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl; and R 37 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2 25 dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, 1-hexyl, may be substituted by OH; or a pharmaceutically-acceptable salt thereof.
72. A compound according to any one of claims 56 through 71 wherein Y is methyl. 30 73. A compound according to any one of claims 56 through 71 wherein W is phenyl-(C- 6 alkylenyl), wherein said phenyl is substituted by one or more groups selected from R 3 0 and R 3 ,.
74. A compound according to claim 73 wherein W is phenylmethyl, wherein said phenyl is 30 31 substituted by one or more groups selected from R and R 35
75. A compound which is: [pyridine triazole names - update or remove]
76. A compound which is: [pyridine tetrazole names - update or remove] 40 77. A compound having the structure: 490 WO 2009/016498 PCT/IB2008/002046 F N N OH NH - OH 0 0 N 78, A compound having the structure: N 'N 0 / -_ N) NH N O N 5
79. A compound having the structure: F /O N!4N O NH -O 0 O N
80. A compound having the structure: F /0 /0 N N NH N O N 10
81. A compound having the structure: F /O N N0 \ / O N 15 491 WO 2009/016498 PCT/IB2008/002046
82. A pharmaceutical composition, comprising a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. 5 83. A method for inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal an MMP-13 inhibiting amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof.
84. A method for treating a disease mediated by an MMP-13 enzyme, comprising 10 administering to a patient suffering from such a disease a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof.
85. A method for treating arthritis, comprising administering to a patient suffering from an arthritis disease a nontoxic antiarthritic effective amount of a compound according to any one of claims 15 1 through 81, or a pharmaceutically acceptable salt thereof.
86. A method for treating osteoarthritis, comprising administering to a patient suffering from osteoarthritis a nontoxic effective amount of a compound according to any one of claims 1 through 79, or a pharmaceutically acceptable salt thereof. 20
87. A method for treating rheumatoid arthritis, comprising administering to a patient suffering from rheumatoid arthritis a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof. 25 88. A method for treating psoriatic arthritis, comprising administering to a patient suffering from psoriatic arthritis a nontoxic effective amount of a compound according to any one of claims 1 through 79, or a pharmaceutically acceptable salt thereof.
89. A method for treating a cancer, comprising administering to a patient suffering from a 30 cancer a nontoxic anti-cancer effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof.
90. A method for treating inflammation, comprising administering to a patient suffering from inflammation a nontoxic effective amount of a compound according to any one of claims 1 35 through 81, or a pharmaceutically acceptable salt thereof.
91. A method for treating chronic obstructive pulmonary disease, comprising administering to a patient suffering from chronic obstructive pulmonary disease a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable 40 salt thereof. 492 WO 2009/016498 PCT/IB2008/002046
92. A method for treating psoriasis, comprising administering to a patient suffering from psoriasis a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof. 5
93. A method for treating asthma, comprising administering to a patient suffering from asthma a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof. 10 94. A method for treating inflammatory bowel disease, comprising administering to a patient suffering from inflammatory bowel disease a nontoxic effective amount of a compound according to any one of claims 1 through 81, or a pharmaceutically acceptable salt thereof. 493
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