CN101090902B

CN101090902B - Cgrp receptor antagonists

Info

Publication number: CN101090902B
Application number: CN200580034796.1A
Authority: CN
Inventors: C·S·伯盖; D·V·保恩; A·W·肖; D·N·阮; 邓正武; T·M·威廉斯; J·P·瓦卡; H·G·塞尔尼克; C·M·波泰格
Original assignee: MERCK
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2004-10-13
Filing date: 2005-10-12
Publication date: 2013-05-29
Anticipated expiration: 2025-10-12
Also published as: CN101090902A; ZA200702309B

Abstract

Compounds of Formula (I): and Formula (II): (where variables R<2>, R<4>, A, B, D, W, X, Y and Z are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

Description

The CGRP receptor antagonist

Background of invention

CGRP (calcitonin-gene-related peptide) is a kind of naturally occurring 37 amino acid peptides, and it changes the processing generation by the tissue specificity of thyrocalcitonin messenger RNA(mRNA), and is distributed widely in maincenter and peripheral nervous system.CGRP mainly is positioned at and feels to import into axoneuron and mediate several biological actions, comprises vasorelaxation action.In rat and the mankind, CGRP is respectively to differ one and three amino acid whose α-and β-formal representation.CGRP-α demonstrates similar biological characteristics with CGRP-β.When being released from cell, CGRP causes its biologically by being combined with specific cell surface receptor, and this combination mainly is and adenylate cyclase (adenylyl cyclase) coupling that activates.People have identified the CGRP acceptor and at few kinds of tissues and cell, comprise in the tissue of brain, cardiovascular, endothelium and unstriated muscle and the cell having carried out its pharmacological evaluation.

According to pharmacological characteristics, these acceptors are divided at least two kinds of hypotypes, are expressed as CGRP ₁And CGRP ₂People [α]-CGRP-(8-37), the CGRP segment of 7-terminal amino acid residues of a kind of disappearance is a kind of selectivity CGRP ₁Antagonist, but the linear analogue of CGRP, diacetylamino methyl halfcystine CGRP ([Cys (ACM) 2,7] CGRP) then is a kind of selectivity CGRP ₂Agonist.CGRP is a kind of effective vasodilator, and it participates in cerebrovascular disease, such as the pathological process of migraine and partially neural headache.In the clinical study, and the CGRP level rising during the discovery migraine in the jugular vein (Goadsby etc., Ann.Neurol., 1990,28,183-187).Acceptor on the CGRP activation intracranial vessel unstriated muscle, cause vasorelaxation to strengthen, this is considered to the major cause (Lance that has a headache during the migraine, Headache Pathogenesis:Monoamines, Neuropeptides, Purines and NitricOxide, Lippincott-Raven Publishers, 1997,3-9).Major arteries in middle meningeal arteries-pachymeninx is subjected to the domination of the Sensory fibre in the gasserian ganglion, and described fiber comprises several neuropeptides, comprises CGRP.In rat, cause the CGRP level to raise to the hormesis of gasserian ganglion, in the people, stimulate the trigeminal nerve system to cause to blush and make that the CGRP level increases in the outside jugular vein (Goadsby etc., Ann.Neurol., 1988,23,193-196).To the dural electricity irritation of rat middle meninx artery diameter is increased, this effect can block by using in advance CGRP (8-37)-a kind of peptide class CGRP antagonist (Williamson etc., Cephalalgia, 1997,17,525-531).In the rat hormesis of gasserian ganglion is accelerated face blood and flows, this effect also suppressed by CGRP (8-37) (Escott etc., Brain Res.1995,669,93-99).Causing face blood to flow to the electricity irritation effect of the gasserian ganglion of America hair monkey (marmoset) increases, this effect is also by the CGRP antagonist BIBN4096BS of non-peptide class blocking-up (Doods etc., Br.J.Pharmacol, 2000,129,420-423).Therefore, CGRP can alleviate, prevent or reverse by the CGRP antagonist the effect of blood vessel.

According to the show, neurone (the Williamson etc. of the vasorelaxation action sensitization trigeminal nerve caudatum (caudalis) of the Midbrain In The Rat film artery of CGRP-mediation, The CGRP Family:Calcitonin Gene-Related Peptide (CGRP), Amylin and Adrenomedullin, Landes Bioscience, 2000,245-247).Equally, the expansion of endocranium blood vessel also makes trigeminal nerve unit become responsive during the migraine.Some relevant migrainous symptoms comprise outside skull pain and facial allodynia, may be sensitization trigeminal nerve unit the result (Burstein etc., Ann.Neurol.2000,47,614-624).The CGRP antagonist may be of value to the effect that alleviates, prevents or reverse the neurone sensitization.

The compounds of this invention can be used as the CGRP antagonist, becomes for humans and animals, particularly the useful medicine of people's the disease that relates to CGRP.This class disease comprises migraine and partially neural headache (Doods, Curr Opin Inves Drugs, 2001,2 (9), 1261-1268; Edvinsson etc., Cephalalgia, 1994,14,320-327); Chronic tension headache (Ashina etc., Neurology, 2000,14,1335-1340); Pain (Yu etc., Eur.J.Pharm., 1998,347,275-282); Chronic pain (Hulsebosch etc., Pain, 2000,86,163-175); Nervosa inflammation and inflammatory pain (Holzer, Neurosci., 1988,24,739-768; Delay-Goyet etc., Acta Physiol.Scanda.1992,146,537-538; Salmon etc., Nature Neurosci., 2001,4 (4), 357-358); Ocular pain (May etc., Cephalalgia, 2002,22,195-196), toothache (Awawdeh etc., Int.Endocrin.J., 2002,35,30-36), non-insulin-dependent diabetes mellitus (NIDDM) (Molina etc., Diabetes, 1990,39,260-265); Vascular disease; Inflammation (Zhang etc., pain, 2001,89,265), sacroiliitis, segmental bronchus overreact, asthma (Foster etc., Ann.NY Acad.Sci., 1992,657,397-404; Schini etc., Am.J.Physiol., 1994,267, H2483-H2490; Zheng etc., J.Virol., 1993,67,5786-5791); Shock, and septicemia (Beer etc., Crit.Care Med., 2002,30 (8), 1794-1798); Protracted opioid abstinencd syndrome (Salmon etc., Nature Neurosci., 2001,4 (4), 357-358); The morphine resistance (Menard etc., J.Neurosci., 1996,16 (7), 2342-2351); Masculinity and femininity hectic fever (Chen etc., Lancet, 1993,342,49; Spetz etc., J.Urology, 2001,166,1720-1723); Allergic dermatitis (Wallengren, Contact Dermatitis, 2000,43 (3), 137-143); Psoriatic; Encephalitis, brain injury, local asphyxia, apoplexy, epilepsy and neurodegenerative disease (Rohrenbeck etc., Neurobiol.of Disease 1999,6,15-34); Tetter (Geppetti and Holzer, Eds., nervosa inflammation, 1996, CRC Press, Boca Raton, FL), nervosa skin rubefaction (neurogenic cutaneous redness), skin rose sample spot and erythema; Tinnitus (Herzog etc., J.Membrane Biology, 2002,189 (3), 225); Inflammatory bowel disease easily swashs property bowel syndrome (Hoffman etc., ScanDinavian Journal ofGastroenterology, 2002,37 (4) 414-422) and urocystitis.Wherein particularly importantly be used for the treatment of or prevent and have a headache, comprise migraine and partially neural headache.Use the clinical study of intravenously administrable BIBN4096BS to provide the CGRP antagonist to be used for the treatment of the strong evidence of migrainous effect.Find thus the CGRP antagonist be a kind of safely and effectively therapeutic agent for migraine (Olesen etc., N.Engl.J.Med., 2004,350 (11), 1104-1110).

The present invention relates to the compound as the CGRP receptors ligand, relate in particular to the CGRP receptor antagonist, their preparation method, therepic use and comprise the pharmaceutical composition of these compounds and use their methods for the treatment of.

Summary of the invention

The present invention relates to as the CGRP receptor antagonist and be used for the treatment of or prevent the relevant disease of CGRP, such as headache, migraine and the nerve formula I compound of having a headache partially:

With formula II compound:

(variable R wherein ², R ⁴, A, B, D, W, X, Y and Z as defined herein).The invention still further relates to the pharmaceutical composition and these compounds and the purposes of composition in prevention or treatment CGRP relative disease that comprise these compounds.

Detailed Description Of The Invention

The present invention relates to the CGRP antagonist, it comprises formula I compound and pharmacologically acceptable salt and diastereomer monomer:

Wherein:

Z is selected from:

A is a key, C (R ²) ₂, O, S (O) _mOr NR ²

B is (C (R ²) ₂) _n

D is independently selected from N and C (R ¹);

R ¹Be independently selected from:

1) H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C _3-6Cycloalkyl and heterocycle, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) aryl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace,

D) heteroaryl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace,

E) heterocycle, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)(CO)NR ¹⁰R ¹¹，

l)O(CO)NR ¹⁰R ¹¹，

m)N(R ⁴)(CO)NR ¹⁰R ¹¹，

n)N(R ¹⁰)(CO)R ¹¹，

o)N(R ¹⁰)(CO)OR ¹¹，

p)SO ₂NR ¹⁰R ¹¹，

q)N(R ¹⁰)SO ₂R ¹¹，

r)S(O) _mR ¹⁰，

s)CN，

t)NR ¹⁰R ¹¹，

U) N (R ¹⁰) (CO) NR ⁴R ¹¹, and

v)O(CO)R ⁴；

2) aryl or heteroaryl, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

I)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)(CO)NR ¹⁰R ¹¹，

l)O(CO)NR ¹⁰R ¹¹，

m)N(R ⁴)(CO)NR ¹⁰R ¹¹，

n)N(R ¹⁰)(CO)R ¹¹，

o)N(R ¹⁰)(CO)OR ¹¹，

p)SO ₂NR ¹⁰R ¹¹，

q)N(R ¹⁰)SO ₂R ¹¹，

r)S(O) _mR ¹⁰，

s)CN，

t)NR ¹⁰R ¹¹，

U) N (R ¹⁰) (CO) NR ⁴R ¹¹, and

v)O(CO)R ⁴；

Any two R independently wherein ¹Optionally form together with coupled one or more atoms and to be selected from C _3-6The ring of cycloalkyl, aryl, heterocycle and heteroaryl;

R ²Be independently selected from:

1) H, C ₀-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C _3-6Cycloalkyl and heterocycle, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)(CO)NR ¹⁰R ¹¹，

l)O(CO)NR ¹⁰R ¹¹，

m)N(R ⁴)(CO)NR ¹⁰R ¹¹，

n)N(R ¹⁰)(CO)R ¹¹，

o)N(R ¹⁰)(CO)OR ¹¹，

p)SO ₂NR ¹⁰R ¹¹，

q)N(R ¹⁰)SO ₂R ¹¹，

r)S(O) _mR ¹⁰，

s)CN，

t)NR ¹⁰R ¹¹，

U) N (R ¹⁰) (CO) NR ⁴R ¹¹, and

v)O(CO)R ⁴；

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)(CO)NR ¹⁰R ¹¹，

l)O(CO)NR ¹⁰R ¹¹，

m)N(R ⁴)(CO)NR ¹⁰R ¹¹，

n)N(R ¹⁰)(CO)R ¹¹，

o)N(R ¹⁰)(CO)OR ¹¹，

p)SO ₂NR ¹⁰R ¹¹，

q)N(R ¹⁰)SO ₂R ¹¹，

r)S(O) _mR ¹⁰，

s)CN，

t)NR ¹⁰R ¹¹，

U) N (R ¹⁰) (CO) NR ⁴R ¹¹, and

v)O(CO)R ⁴；

Wherein be positioned at any two R independently on same atom or the adjacent atom ²Optionally form together and be selected from following ring: cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrimidyl, pyrazinyl, pyrryl, pyrrolinyl, morpholinyl, parathiazan, parathiazan S-oxide compound, parathiazan

S-dioxide, azetidinyl, pyrrolidyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, furyl, dihydrofuran base, dihydro pyranyl and piperazinyl;

R ¹⁰And R ¹¹Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and benzyl, it is unsubstituted or by halogen, hydroxyl or C ₁-C ₆Alkoxyl group replaces, wherein R ¹⁰And R ¹¹Randomly form together and be selected from following ring: azetidinyl, pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described ring are unsubstituted or are selected from independently of one another R by 1-5 ⁴Substituting group replace;

R ⁴Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and benzyl, it is unsubstituted or by halogen, hydroxyl or C ₁-C ₆Alkoxyl group replaces;

W is O, NR ⁴Or C (R ⁴) ₂

X is C or S;

Y is O, (R ⁴) ₂, NCN, NSO ₂CH ₃Or NCONH ₂, perhaps when X was S, Y was O ₂

R ⁶Be independently selected from H and:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)(CO)NR ¹⁰R ¹¹，

l)O(CO)NR ¹⁰R ¹¹，

m)N(R ⁴)(CO)NR ¹⁰R ¹¹，

n)N(R ¹⁰)(CO)R ¹¹，

o)N(R ¹⁰)(CO)OR ¹¹，

p)SO ₂NR ¹⁰R ¹¹，

q)N(R ¹⁰)SO ₂R ¹¹，

r)S(O) _mR ¹⁰，

s)CN，

t)NR ¹⁰R ¹¹，

U) N (R ¹⁰) (CO) NR ⁴R ¹¹, and

v)O(CO)R ⁴；

J is a key, C (R ⁶) ₂, O or NR ⁶

V is selected from a key, C (R ⁶) ₂, O, S (O) _m, NR ⁶, C (R ⁶) ₂-C (R ⁶) ₂, C (R ⁶)=C (R ⁶), C (R ⁶) ₂-N (R ⁶), C (R ⁶)=N, N (R ⁶)-C (R ⁶) ₂, N=C (R ⁶) and N (R ⁶)-N (R ⁶);

G-L is selected from: N, N-C (R ⁶) ₂, C=C (R ⁶), C=N, C (R ⁶), C (R ⁶)-C (R ⁶) ₂, C (R ⁶)-C (R ⁶) ₂-C (R ⁶) ₂, C=C (R ⁶)-C (R ⁶) ₂, C (R ⁶)-C (R ⁶)=C (R ⁶), C (R ⁶)-C (R ⁶) ₂-N (R ⁶), C=C (R ⁶)-N (R ⁶), C (R ⁶)-C (R ⁶)=N, C (R ⁶)-N (R ⁶)-C (R ⁶) ₂, C=N-C (R ⁶) ₂, C (R ⁶)-N=C (R ⁶), C (R ⁶)-N (R ⁶)-N (R ⁶), C=N-N (R ⁶), N-C (R ⁶) ₂-C (R ⁶) ₂, N-C (R ⁶)=C (R ⁶), N-C (R ⁶) ₂-N (R ⁶), N-C (R ⁶)=N, N-N (R ⁶)-C (R ⁶) ₂And N-N=C (R ⁶);

Q is independently selected from:

(1)＝C(R ^7a)-，

(2)-C(R ^7a) ₂-，

(3)-C(＝O)-，

(4)-S(O) _m-，

(5)=N-, and

(6)-N(R ^7a)-；

T is independently selected from:

(1)＝C(R ^7b)-，

(2)-C(R ^7b) ₂-，

(3)-C(＝O)-，

(4)-S(O) _m-，

(5)=N-, and

(6)-N(R ^7b)-；

R ³Be independently selected from H, replacement or unsubstituted C ₁-C ₃Alkyl, F, CN and CO ₂R ⁴R ^7aAnd R ^7bBe selected from independently of one another R ², R wherein ^7aAnd R ^7bRandomly form together with coupled one or more atoms and to be selected from C _3-6The ring of cycloalkyl, aryl, heterocycle and heteroaryl, described ring are unsubstituted or are independently selected from R by 1-10 ⁶Substituting group replace;

P is 0 to 2q+1 (for the substituting group with q carbon atom);

M is 0,1 or 2;

N is 0 or 1;

S is 1,2 or 3.

The further embodiment of the present invention is the CGRP antagonist of formula I, and it comprises formula Ia compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

A is a key, C (R ²) ₂, O, S (O) _mOr NR ²

B is (C (R ²) ₂) _n

N is 0 or 1; And

D, R ², R ⁴, W, Z and m be suc as formula defining among the I.

Another embodiment of the invention is the CGRP antagonist of formula I, and it comprises formula Ib compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

D, R ², R ⁴, W, Z and m be suc as formula defining among the I.

Another embodiment of the invention is the CGRP antagonist of formula I, and it comprises formula Ic compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

A is C (R ²) ², O, S (O) _mOr NR ²

D, R ², R ⁴, W, Z and m be suc as formula defining among the I.

Another embodiment of the invention is the CGRP antagonist of formula I, and it comprises formula Id compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

R ¹, R ², R ⁴, W, Z and m be suc as formula defining among the I.

Another embodiment of the invention is the CGRP antagonist of formula I, and it comprises formula Ie compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

R ¹, R ², R ⁴, W, Z and m be suc as formula defining among the I.

Another embodiment of the invention is the CGRP antagonist of formula I, and it comprises formula If compound and pharmacologically acceptable salt and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

R ¹, R ², R ⁴, W, Z and m be suc as formula defining among the I.

The further embodiment of the present invention is CGRP antagonist and pharmacologically acceptable salt and the steric isomer monomer of formula Ia-Ie, wherein:

R1 is selected from:

1) H, C ₁-C ₆Alkyl, C _3-6Cycloalkyl and heterocycle, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) aryl, it is not replace or the individual R that is independently selected from of 1-5 ⁴Substituting group replace,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

M) O (CO) R ⁴And

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴；

R ²Be selected from:

1) H, C ₀-C ₆Alkyl, C ₂-C ₆Alkynyl, C _3-6Cycloalkyl and heterocycle, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) aryl, it is unsubstituted or is independently selected from R by 1-5 ⁴Substituting group replace,

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)S(O) _mR ⁴，

l)CN，

M) NR ¹⁰R ¹¹, and

N) O (CO) R ⁴And

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴，

Wherein be positioned at any two R independently on same atom or the adjacent atom ²Optionally form together and be selected from following ring: cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl oxazolyl oxazolinyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrimidyl, pyrazinyl, pyrryl, pyrrolinyl, morpholinyl, parathiazan, parathiazan S-oxide compound, parathiazan S-dioxide, azetidinyl, pyrrolidyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, furyl, the dihydrofuran base, dihydro pyranyl and piperazinyl;

R ¹⁰And R ¹¹Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and benzyl, it is unsubstituted or by halogen, hydroxyl or C ₁-C ₆Alkoxyl group replaces, wherein R ¹⁰And R ¹¹Randomly form together and be selected from following ring: azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl, described ring are unsubstituted or are selected from independently of one another R by 1-5 ⁴Substituting group replace;

W is O, NR ⁴Or C (R ⁴) ₂

R ⁶Be independently selected from H and:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

M) O (CO) R ⁴And

J is a key, C (R ⁵) ₂, O or NR ⁵, and V is a key, C (R ⁶) ₂, O, S (O) _m, NR ⁶, C (R ⁶) ₂-C (R ⁶) ₂, C (R ⁶)=C (R ⁶), C (R ⁶) ₂-N (R ⁶), C (R ⁶)=N, N (R ⁶)-C (R ⁶) ₂, N=C (R ⁶) or N (R ⁶)-N (R ⁶), work as this moment:

J is a key, and V is a key and Z when being Z1, forms the following formula structure:

J is a key, and V is a key, Z be Z1 and T be-C (=O)-, form the following formula structure:

J is a key and Z when being Z1, forms the following formula structure:

V is a key and Z when being Z1, forms the following formula structure:

G-L is N, and Z forms the following formula structure when being Z2:

G-L is N-C (R ⁶) ₂, and Z forms the following formula structure when being Z2:

G-L is C=C (R ⁶), and Z forms the following formula structure when being Z2:

G-L is C=N, and Z forms the following formula structure when being Z2:

G-L is N-C (R ⁶) ₂-C (R ⁶) ₂, and Z forms the following formula structure when being Z2:

Q is independently selected from:

(1)＝C(R ^7a)-，

(2)-C(R ^7a) ₂-，

(3)-C(＝O)-，

(4)-S(O) _m-，

(5)=N-, and

(6)-N(R ^7a)-；

T is independently selected from:

(1)＝C(R ^7b)-，

(2)-C(R ^7b) ₂-，

(3)-C(＝O)-，

(4)-S(O) _m-，

(5)=N-, and

(6)-N(R ^7b)-；

R ³Be independently selected from H, replacement or unsubstituted C ₁-C ₃Alkyl, F, CN and CO ₂R ⁴R ^7aAnd R ^7bBe selected from independently of one another R ², R wherein ^7aAnd R ^7bRandomly form with the one or more atoms that link to each other with it and to be selected from C _3-6The ring of cycloalkyl, aryl, heterocycle and heteroaryl, described ring be unsubstituted or by 1-10 each is independently selected from R separately ⁶Substituting group replace;

P is 0-2q+1 (for the substituting group with q carbon atom);

M is 0-2;

S is 1-3.

The CGRP antagonist that other embodiments of the present invention are formula Ia-Ie and pharmacologically acceptable salt thereof and steric isomer monomer, wherein

R ¹Be selected from:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) phenyl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace,

D) heteroaryl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: imidazoles, isoxazole, oxazole, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine and thiazole;

E) heterocycle, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace, and wherein heterocycle is selected from: azetidine, diox, dioxolane, morpholine, trimethylene oxide, piperazine, piperidines, tetramethyleneimine, tetrahydrofuran (THF) and tetrahydropyrans;

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)CN，

l)NR ¹⁰R ¹¹，

m)O(CO)R ⁴；

2) aryl or heteroaryl are selected from: phenyl, imidazoles, isoxazole, oxazole, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine and thiazole, and it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰RH ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴；

R ²Be selected from:

1) H, C ₀-C ₆Alkyl, C _3-6Cycloalkyl and heterocycle, it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

D) heteroaryl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, isoxazole, oxazole, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, thiazole, thiophene and triazole;

E) heterocycle, it is not replace or the individual R that is independently selected from of 1-5 ⁴Substituting group replace, and wherein heterocycle is selected from: azetidine, imidazolidine, tetrahydroglyoxaline, isoxazoline, isoxazole alkyl, morpholine, oxazoline, oxazolidine, trimethylene oxide, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran (THF), tetrahydropyrans, thiazoline and thiazolidine;

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

M) O (CO) R ⁴And

2) aryl or heteroaryl, they are selected from: phenyl, benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, isoxazole, oxazole, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, thiazole, thiophene and triazole, and it is unsubstituted or is independently selected from following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴，

Wherein be positioned at any two R independently on same atom or the adjacent atom ²Optionally form together and be selected from following ring: cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl oxazolyl oxazolinyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrimidyl, pyrazinyl, pyrryl, pyrrolinyl, morpholinyl, parathiazan, parathiazan S-oxide compound, parathiazan S-dioxide, azetidinyl, pyrrolidyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, furyl, the dihydrofuran base, dihydro pyranyl and piperazinyl

R ¹⁰And R ¹¹Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and benzyl, it is unsubstituted or by halogen, hydroxyl or C ₁-C ₆Alkoxyl group, wherein R ¹⁰And R ¹¹Optionally form together and be selected from following ring: azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl, these rings are unsubstituted or are selected from independently of one another R by 1-5 ⁴Substituting group replace;

R ⁴Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and phenyl, it is unsubstituted or by hydroxyl or C ₁-C ₆Alkoxyl group replaces;

W is NR ⁴Or C (R ⁴) ₂

R ⁶Be independently selected from H and:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴；

J is a key, and V is a key, and Z is Z1, and Q is-N (R ^7a)-, and T be-C (=O)-, form thus the following formula structure:

J is a key, and V is a key, and Z is Z1, and Q is-C (R ^7a) ₂-, and T be-C (=O)-, form thus the following formula structure:

J is a key, and V is a key, and Z is Z1, and Q is-N=, and T is=C (R ^7b)-, forms the following formula structure thus:

J is a key, and V is a key, and Z is Z1, and Q is-C (R ^7a) ₂-, and T is-C (R ^7b) ₂-, form thus the following formula structure:

J is a key, and V is a key, and Z is Z1, and Q is-C (R ^7a)=, T is=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms benzene, pyridine or diazine ring together, forms thus the structure of one of following formula:

J is a key, and V is C (R ⁶) ₂, Z is Z1, Q is-C (R ^7a)=, T is=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms benzene or pyridine ring together, forms thus the structure of one of following formula:

J is O, and V is a key, and Z is Z1, and Q is-C (R ^7a)=, T is=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms benzene or pyridine ring together, forms thus the structure of one of following formula:

G-L is N, and Z is Z2, and Q is-C (R ^7a) ₂-, and T is-C (R ^7b) ₂-, form thus the following formula structure:

G-L is N, and Z is Z2, and Q is-C (R ^7a)=, and T are=C (R ^7b)-, forms the following formula structure thus:

G-L is N, and Z is Z2, and Q is-N=, and T is=C (R ^7b)-, forms the following formula structure thus:

G-L is N, and Z is Z2, and Q is-C (R ^7a) ₂-, and T be-C (O)-, form thus the following formula structure:

G-L is C=C (R ⁶), Z is Z2, Q is-C (R ^7a)=and T be=C (R ^7b)-, forms the following formula structure thus:

G-L is C=C (R ⁶), Z is Z2, Q is-C (R ^7a)=and T be=N-to form thus the following formula structure:

G-L is C=C (R ⁶), Z is Z2, and Q is-and N=and T be=C (R ^7b)-, forms the following formula structure thus:

G-L is C=N, and Z is Z2, and Q is-C (R ^7a)=and T be=C (R ^7b)-, forms the following formula structure thus:

G-L is N, and Z is Z2, and Q is-C (R ^7a)=, and T are=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms benzene, pyridine or diazine ring together, forms thus the structure of one of following formula:

G-L is N-C (R ⁶) ₂, Z is Z2, Q is-C (R ^7a)=, and T are=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms benzene or pyridine ring together, forms thus the structure of one of following formula:

G-J is C=N, and Z is Z2, and Q is-C (R ^7a)=, and T are=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms phenyl ring together, forms thus the structure of one of following formula:

G-L is C=C (R ⁶), Z is Z2, Q is-C (R ^7a)=and T be=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms phenyl ring together, forms thus the structure of one of following formula:

G-L is N-C (R ⁶) ₂-C (R ⁶) ₂, Z is Z2, Q is-C (R ^7a)=, and T are=C (R ^7b)-, and and R ^7aAnd R ^7bThe atom that links to each other forms phenyl ring together, forms thus the structure of one of following formula:

R ³Be independently selected from H, replacement or unsubstituted C ₁-C ₃Alkyl, F, CN and CO ₂R ⁴

R ^7aAnd R ^7bBe selected from independently of one another R ², R wherein ^7aAnd R ^7bRandomly form with the one or more atoms that link to each other with it and to be selected from C _3-6The ring of cycloalkyl, aryl, heterocycle and heteroaryl, it is unsubstituted or is independently from each other R by 1-10 ⁶Group replace;

P is 0-2q+1, for the substituting group with q carbon atom;

M is 0-2;

S is 1-3.

Another embodiment of the invention comprises CGRP antagonist and pharmacologically acceptable salt and the diastereomer monomer of formula II:

Wherein:

B, J, Q, T, V, W, X, Y, R ¹, R ², R ³And R ⁴Suc as formula defining among the I.

Should be appreciated that one or more above-mentioned structural formulas or substituting group are described when having the substituting group of a plurality of same names, these variables and each have the variable of same names can be identical or different.For example, R has been described four times among the formula I ², each R among the formula I so ²Can be R independently ²Undefined any minor structure.For determining structure, the invention is not restricted to wherein each R ²All must be identical structure or minor structure.Be not always the case for any variable that occurs repeatedly in structural formula or the minor structure.

The present invention can comprise one or more asymmetric centers, therefore can exist with racemic modification or raceme mixture, enantiomorph monomer, non-enantiomer mixture and diastereomer monomeric form.According to the character of different substituents on the molecule, also can there be other asymmetric center.Each this asymmetric center will form two kinds of optical isomers independently, so the scope of the invention comprises mixture and pure or the partially purified compound of all possible optical isomer and diastereomer.The present invention also comprises these compounds of all these type of isomeric forms.

Compounds more as herein described also comprise olefinic double bond, and unless otherwise indicated, the present invention also is intended to comprise the geometrical isomer of E and Z formula.

Synthetic or its chromatographic separation separately of these diastereomers can realize by means known in the art by proper method disclosed herein.Their absolute stereo chemistry can be determined by the X-ray crystallography method of crystallized product or crystallization of intermediate, if necessary, can will measure after their reagent derivation with the asymmetric center that comprises known absolute configuration.

If necessary, racemic mixture and then enantiomer separation monomer that can first separating compound.Separation can be carried out by means commonly known in the art, and for example racemic mixture and the enantiopure compound coupling with compound forms non-enantiomer mixture, then adopts standard method, such as fractional crystallization or chromatographic separation diastereomer monomer.Linked reaction uses the acid of enantiomer-pure or alkali to form salt usually.Then non-enantiomer derivative is converted into pure enantiomorph by the chirality residue that cracking adds.The racemic mixture of the compounds of this invention also can directly separate by utilizing chiral stationary phase to pass through chromatographic process, and the method is well known in the art.

Perhaps, any enantiomorph of compound can pass through methods known in the art, obtains by Stereoselective synthesizing process with optical purity raw material or the reagent of configuration known.

This area professional and technical personnel is with clear, and said each substituting group or its combination that is used to form ring is not can both form ring structure under every kind of situation or situation.And, even those substituting groups that can form ring can form or not form ring structure under each situation or situation.

This area professional and technical personnel is also with clear, and halo used herein or halogen comprise chlorine, fluorine, bromine and iodine.

" alkyl " used herein refers to not have straight chain, side chain and the ring texture of two keys or triple bond.Therefore, C _1-6Alkyl is defined as having the linearity of 1,2,3,4,5 or 6 carbon atom or the group that branch arranges, for example C _1-6Alkyl specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group and hexyl." cycloalkyl " is its alkyl that has partly or entirely formed the ring of three or more atoms.C ₀Or C ₀Alkyl is defined as directly continuous covalent linkage.

" aryl " used herein refers to that each ring is at most the stable monocycle of 7 yuan of rings or the carbocyclic ring of two rings, and wherein at least one ring is aromatic ring.The example of this class aryl comprises phenyl, naphthyl, tetralyl, 2,3-indanyl or xenyl.

Unless otherwise indicated, 5-7 unit's monocycle that term used herein " heterocycle " or " heterocycle " expression are stable or bicyclic heterocycle system of 8-11 unit, it can be saturated or unsaturated, and formed by carbon atom and 1-4 heteroatoms that is selected from N, O and S, and wherein the heteroatoms of nitrogen and sulphur is optionally oxidized, nitrogen heteroatom is optionally quaternized, and comprises the dicyclo that wherein any as defined above heterocycle and phenyl ring condense.Heterocycle can be connected to form rock steady structure by any heteroatoms or carbon atom position.The example of this class heterocyclic group includes, but not limited to azetidine, chroman, dihydrofuran, dihydropyrane, diox, dioxolane, six hydrogen azepines

, imidazolidine, imidazolidone, tetrahydroglyoxaline, imidazolone, indoline, heterochromatic full, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazole alkyl, morpholine, morpholone mai, oxazoline, oxazolidine, oxazolidone, trimethylene oxide, 2-oxo six hydrogen azepines

, 2-oxa-piperazine, 2-oxa-piperidines, 2-oxa-tetramethyleneimine, piperazine, piperidines, pyrans, pyrazolidine, pyrazoline, tetramethyleneimine, pyrroline, quinine pyridine, tetrahydrofuran (THF), tetrahydropyrans, parathiazan, thiazoline, thiazolidine, parathiazan and N-oxide compound thereof.

Unless otherwise indicated, the 5-7 unit's monocycle that comprises an aromatic ring that " heteroaryl " used herein expression is stable or 9-10 unit condensed-bicyclic ring system, its any ring can be saturated or unsaturated, such as pyridyl, and it is comprised of carbon atom and 1-4 heteroatoms that is selected from N, O and S, and wherein the heteroatoms of nitrogen and sulphur is optionally oxidized, and nitrogen heteroatom is optionally quaternized, and comprises the dicyclo that wherein any as defined above heterocycle and phenyl ring condense.Heterocycle can be connected to form rock steady structure by any heteroatoms or carbon atom position.The example of this class heterocyclic group comprises, but be not limited to benzoglyoxaline, benzisothiazole, benzoisoxazole, cumarone, benzothiazole, thiophene, benzotriazole, benzoxazole, carboline, cinnolines, furans, furazan, imidazoles, indazole, indoles, indolizine, isoquinoline 99.9, isothiazole, isoxazole, naphthyridines, oxadiazole, oxazole, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, quinazoline, quinoline, quinoxaline, tetrazolium, thiadiazoles, thiazole, thiophene, triazine, triazole and N-oxide compound thereof.

Such as C ₁-C ₆Term in the alkoxyl group " alkoxyl group " refers to the alkoxyl group of straight chain, side chain and the cyclic configuration of 1-6 carbon atom.Example comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, cyclohexyloxy etc.

Phrase used herein " pharmaceutically useful " refers to, those are suitable for contacting with human and animal's tissue and do not have excessive toxicity, pungency and anaphylaxis or other problems or complication in rational medical judgment scope, are equivalent to have compound, raw material, composition and/or the formulation of reasonable benefit/dangerous ratio.

" pharmacologically acceptable salt " used herein refers to the derivative that parent compound wherein obtains by the salt that is made into its acid or alkali.The example of pharmacologically acceptable salt includes, but not limited to basic group, such as mineral acid or the organic acid salt of amine; Acidic-group is such as the alkali salt of carboxylic acid or organic salt etc.Pharmacologically acceptable salt comprises, for example, and conventional non-toxic salt or the quaternary ammonium salt of the parent compound that is formed by nontoxic organic acid or mineral acid.For example, the non-toxic salt of this class routine comprises those by mineral acid, the salt that example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc. obtain; With by organic acid, such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, palmitinic acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, Aspirin, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethionic acid, oxalic acid, isethionic acid etc.

Under specific circumstances, the numerical value of the particular variables of existence defines with respect to the amount of carbon atom that exists.For example, variable " p " sometimes by as give a definition: " p is 0-2q+1, for having the substituting group of q carbon atom ".Wherein substituting group is " (F) _pC _1-3Alkyl ", this shows when having a carbon atom, existence 2 (1)+1=3 fluorine atom.When having 2 carbon atoms, there is 2 (2)+1=5 fluorine atom, when having 3 carbon atoms, there is 2 (3)+1=7 fluorine atom.

When having variable G and L or being described to " G-L ", expression G and L represent a specific structure division together.G-L can represent an annular atoms or different a plurality of annular atomses of arranging.For example G-L is defined as single annular atoms N sometimes herein, sometimes is defined as a plurality of annular atoms N-C (R ⁶) ₂, C=C (R ⁶) etc.

When compound of the present invention is when alkalescence, can be by pharmaceutically useful non-toxic acid, comprise that mineral acid and organic acid make salt.This class acid comprises acetic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, palmitinic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.In one aspect of the invention, this class salt is citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric salt.Should be clear, the formula I compound of mentioning among the present invention also comprises its pharmacologically acceptable salt.

Illustrate the present invention with embodiment and compound disclosed herein.Particular compound of the present invention comprises and is selected from disclosed compound and pharmacologically acceptable salt and diastereomer monomer in the following example.

Motif compound of the present invention can be applicable to the antagonism patient, and such as the method for the mammiferous CGRP acceptor of this antagonism of need, the method comprises the compounds of this invention of using significant quantity.The present invention relates to compound disclosed herein as the purposes of CGRP receptor antagonist.Method of the present invention can also be treated multiple other Mammalss except treating outside the primate, particularly people.

Another embodiment of the invention relates to a kind for the treatment of, control, improve or alleviate the patient with the receptor related disease of CGRP or the method for illness, the method comprises the CGRP receptor agonist compounds to patient's administering therapeutic significant quantity.

The invention still further relates to a kind of method for preparing the medicine of CGRP receptor active among the antagonism human and animal, comprise the compounds of this invention is combined with pharmaceutically acceptable carrier or thinner.

The object of the inventive method treatment normally its CGRP receptor active needs the Mammals of antagonism, for example people of sex.Term " treatment significant quantity " refers to that will make tissue, system, animal or human that investigator, animal doctor, medical doctor or other clinical staff are thought show the amount of the motif compound of biology or medical response.The illness that term used herein " treatment " refers to treat or prophylactic treatment is mentioned particularly has tendency to suffer from the patient's of this class disease or illness illness.

Term used herein " composition " is intended to comprise the product of the specific composition of specified quantitative, and any product that is directly or indirectly obtained by the combination of the specific composition of specified quantitative.This term relevant with pharmaceutical composition be intended to comprise and comprise one or more active ingredients and as the product of one or more inert components of carrier, and by the combination of two or more compositions arbitrarily, compound or assemble or by the reaction of the other types of one or more compositions or any product that interacts and directly or indirectly form.Therefore, pharmaceutical composition of the present invention comprises any composition that is worth by mixing the compounds of this invention and pharmaceutically acceptable carrier." pharmaceutically acceptable " refers to that carrier, thinner or vehicle must be safe from harm with other component compatibility of preparation and for its recipient.

Term administering " compound (noun and/or verb form) is interpreted as referring to the individuality of this treatment of need is provided the prodrug of the compounds of this invention or the compounds of this invention.

The compounds of this invention can be confirmed by methods known in the art as the active effectiveness of CGRP receptor antagonist.Following mensuration ¹²⁵The functional antagonistic action of the restraining effect of I-CGRP and receptors bind and CGRP acceptor:

Natural receptor is in conjunction with mensuration: ¹²⁵The combination of acceptor is carried out according to the method (Edvinsson etc., (2001) Eur.J.Pharmacol.415,39-44) of describing substantially in I-CGRP and the SK-N-MC cytolemma.Put it briefly, film (25 μ g) is being comprised 10pM ¹²⁵[10mM HEPES, pH 7.4,5mM MgCl for the 1ml binding buffer liquid of I-CGRP antagonist ₂With 0.2% bovine serum albumin (BSA)] in be incubated., stop measuring with 3 hours GFB glass fibre screen plate (Millipore) of 0.5% polymine retardance by filtering after 3 hours in the room temperature insulation.With screen plate with ice-cold mensuration damping fluid washing three times after, at air drying.Add scintillation solution (50 μ l) and count radioactivity at Topcount (Packard Instrument).By using Prism to carry out data analysis and use Cheng-Prusoff equation (Cheng﹠amp; Prusoff (1973) Biochem.Pharmacol.22,3099-3108) determine K _i

The functional analysis of natural receptor: the SK-N-MC cell is supplemented with in the minimal essential medium (MEM) of 10% foetal calf serum, 2mM 1-L-glutamic acid, 0.1mM non-essential amino acid, 1mM Sodium.alpha.-ketopropionate, 100 units/ml penicillin and 100 μ g/ml Streptomycin sulphates therein, at 37 ℃, 95% humidity and 5%CO ₂Lower growth.Measure for carrying out cAMP, before mensuration with cell with 5 * 10 ⁵The density of individual cells/well is tiled in 96 holes, and the coated culture plate (Becton-Dickinson) of poly--D-Lys is gone up and was cultivated about 18 hours.After (PBS, σ) wash with phosphate buffered saline (PBS) with cell, in the MEM that does not contain serum, cultivated in advance 30 minutes at 37 ℃ with 300 μ M isobutyl methylxanthines.Add antagonist and cell cultures after 10 minutes, is added CGRP again.After cultivating 15 minutes, cell carries out cAMP mensuration with the PBS washing and according to the scheme of manufacturer recommendation again.Be defined as maximal stimulation on the basis with 100nM CGRP.Use Prism to generate dose-response curve.Calculating dose-ratio (DR) is also drawn full Schild with it and is schemed (Arunlakshana﹠amp; Schild (1959) Br.J.Pharmacol.14,48-58).

Recombinant receptor: CRLR (Genbank adds numbering [0237] L76380) is subcloned among the expression vector pIREShyg2 (BD Biosciences Clontech) as 5 ' NheI and 3 ' Pmel segment.People RAMP1 (Genbank adds numbering AJ001014) is subcloned among the expression vector pIRESpuro2 (BD Biosciences Clontech) as 5 ' NheI and 3 ' NotI segment.With 293 cell (human embryonic kidney cells; ATCC#CRL-1573) in being supplemented with the DMEM that contains 4.5g/L glucose, 1mM Sodium.alpha.-ketopropionate and 2mM L-glutamic acid of 10% foetal calf serum (FBS), 100 units/mL penicillin and 100ug/ml Streptomycin sulphate, under 37 ℃ and 95% humidity, cultivate.In HBSS, use 0.25% trypsin treatment that contains 0.1%EDTA that cell is carried out time cultivation.At 75cm ²In the flask, generate stable clone by common transfection 10 μ gDNA and 30 μ gLipofect amine 2000 (Invitrogen).Expression with the common transfection CRLR of equivalent and RAMP1 makes up.After the transfection 24 hours, diluting cells and at bringing Selection In property of second day substratum (growth medium+300 μ g/ml Totomycin and 1 μ g/ml tetracycline).By using FACS Vantage SE (Becton Dickinson) to carry out unicellular deposition, generate cloned cell line.For carrying out cell proliferation, growth medium is adjusted to 150 μ g/ml Totomycin and 0.5 μ g/ml tetracycline.

Recombinant receptor is in conjunction with mensuration: the cell that will express recombinant human CRLR/RAMPl is caught with the PBS washing and with the capture buffer liquid that contains 50mM HEPES, 1mM EDTA and adequate proteins enzyme inhibitors (Roche).Cell suspension breaks and centrifugation after birth under 48,000g with the laboratory homogenizer.Be suspended in again in the capture buffer liquid that is added with 250mM sucrose precipitation and-70 ℃ of storages.Measure for carrying out combination, 10 μ g after births are being contained 10pM ¹²⁵(10mMHEPES, pH 7.4,5mM MgCl for the 1ml binding buffer liquid of I-hCGRP (Amersham Biosciences) and antagonist ₂And 0.2%BSA) is incubated 3 hours in room temperature in.Measure with 96 hole GFB glass fibre screen plates (Millipore) termination of 0.05% polymine retardance by filtering.Filtrate is washed three times with ice-cold mensuration damping fluid (10mM HEPES, pH 7.4).The adding scintillation solution is also counted culture plate on Topcount (Packard).Measure non-specific binding and by utilizing nonlinear least square to make the CPM data fitting of combination in the binding constants (K that establishes an equation definite down _i) carry out data analysis:

Wherein Y observe in conjunction with CPM, Y _MaxMiddle in conjunction with number, Y _MinThe non-specific binding number, (Y _Max-Y _Min) be the specific binding number, %I _MaxMaximum percent inhibition, %I _MinMinimum percent inhibition, K _dIt is the binding constants by the acceptor radioligand of Hot saturation experiments mensuration.

Recombinant receptor functional examination: before mensuration, cell is tiled in the complete growth medium of the coated culture plate (Corning) of the poly-D-Lys in 96 holes with the density of 85,000 cells/well and cultivated about 19 hours.Cell is with not containing in serum/low PROTEIN C ellgro perfect medium (Cellgro Complete Serum-Free/Low-Protein medium) (Mediatech, Inc.) under 37 ℃ and 95% humidity cultivation 30 minutes with inhibitor what contain Pidolidone and 1g/LBSA after the PBS washing.The concentration of isobutyl methylxanthine with 300 μ M is added in the cell and at 37 ℃ to descend to be incubated 30 minutes.Be added in cell with the concentration of 0.3nM people α-CGRP and it was cultivated 5 minutes at 37 ℃.Behind [α]-CGRP irritation cell, with PBS washing and utilize two sections mensuration schemes of manufacturers's suggestion (cAMP SPA directly shelters the mensuration system; RPA 559; Amersham Biosciences) carrying out cAMP measures.Draw dose response curve and by equation y=((a-d)/(1+ (x/c) ^bIC is determined in the 4-parameter logic match (logistic fit) of)+d definition ₅₀Value, wherein y=reaction, x=dosage, the maximum reaction of a=, d=minimal reaction, c=change point, b=slope.

Especially, the following example compound has CGRP receptor antagonist activity, usually their K in aforementioned mensuration _iOr IC ₅₀Value is less than about 50 μ M.This result shows that the compounds of this invention is as the intrinsic activity of CGRP receptor antagonist.

The present invention can become for the human and animal it as the character of CGRP antagonist, but the medicine of the human illness relevant with CGRP particularly.

The compounds of this invention has treatment, prevention, improvement, control is a kind of or the following illness of inertia or disease or alleviate its dangerous beneficial functional: headache; Migraine; Partially neural headache; Chronic tension headache; Pain; Chronic pain; Nervosa inflammation and inflammatory pain; Neuropathic pain; Ocular pain; Toothache; Diabetes; Non-insulin-dependent diabetes mellitus (NIDDM); Vascular disease; Inflammation; Sacroiliitis; Segmental bronchus overreaction, asthma; Shock; Septicemia; Protracted opioid abstinencd syndrome; Morphine disease; The masculinity and femininity hectic fever; Allergic dermatitis; Psoriatic; Encephalitis; Brain injury; Epilepsy; Neurodegenerative disease; Tetter; Nervosa skin rubefaction, skin rose sample spot and erythema; Inflammatory bowel disease easily swashs property bowel syndrome and urocystitis; And other can be by the illness of the treatment of antagonism CGRP acceptor or prevention.Wherein particularly importantly be used for the treatment of or prophylactic treatment headache, migraine and partially neural headache.

Motif compound of the present invention also can be used for preventing, treat, control, improve or alleviating disease described herein, illness and indication or its danger.

Motif compound of the present invention also can be united for preventing, treat, control, improve or alleviating aforementioned diseases, illness or indication or its danger with other drug.

The compounds of this invention can be united with one or more other drugs and is used for the treatment of, prevent, control, improve formula I compound or the medicable disease of other drug tool or indication or its danger, and wherein the coupling medicine is safer or more effective than the independent use of a kind of medicine.This class other drug can be used with its usual amounts and formula I compound simultaneously or sequentially by its approach commonly used.When formula I compound and one or more other drugs use simultaneously, preferably comprise the pharmaceutical composition of the unit dosage forms of other drug and formula I compound.Yet combination therapy can comprise that also its Chinese style I compound and one or more other drugs are the treatments with the administration of different closed assembly time scheme.Should be taken into account that when uniting when using with one or more its active ingredients, the compounds of this invention and other active ingredients can use by the dosage when being lower than it and using separately.Therefore pharmaceutical composition of the present invention comprises except comprising formula I compound, also contains those of one or more other active ingredients.

For example, the compounds of this invention can with following drug combination: antimigraine drug such as Ergotamine and dihydroergotamine or other serotonin agonists, particularly 5-HT _1B/1DAgonist such as sumatriptan, naratriptan, Zomitriptan, according to drawing Qu Tan, almotriptan, fluorine to cut down the general Qu Tan of Pu Tan, Donitriptan and Leeza, 5-HT _1DAgonist such as PNU-142633 and 5-HT _1FAgonist such as LY334370; Cyclooxygenase inhibitors, for example selective cyclooxygenase-2 inhibitor such as rofecoxib, L-791456, celecoxib, valdecoxib or paracoxib; Nonsteroidal anti-inflammatory agent or cell factor inhibiting anti-inflammatory agent, such as compound Ibuprofen BP/EP, Ketoprofen, fenoprofen calcium, Naproxen Base, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, R-ETODOLAC, vialidon, meclofenamic acid, Tecramine, tolfenamic acid, diclofenac sodium, Oxaprozin, azapropazone, nimesulide, Maxicom, tenidap, etanercept, tolmetin, Phenylbutazone, crovaril, diflunisal, salsalate, olsalazine or sulfasalazine etc.; Perhaps glucocorticosteroid.Similarly, the compounds of this invention also can with pain killer, such as acetylsalicylic acid, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, Methadyl Acetate, Lepetan or morphine coupling.

In addition, the compounds of this invention can also with following drug combination: the interleukin inhibitor, such as interleukin-1 inhibitor; Nk 1 receptor antagonist such as aprepitant; Nmda antagonist; The NR2B antagonist; Bradykinin-1 receptor antagonist; Adenosine a1 receptor agonists; Sodium channel inhibitor such as lamotrigine; Opiate agonist such as left Methadyl Acetate or Methadyl Acetate; Lipoxidase inhibitor such as 5-lipoxidase inhibitor; α receptor antagonist such as Indoramine; The α receptor stimulant; The vanilloid receptor antagonist; Renin inhibitor; The granzyme B inhibitor; The Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 antagonist; Endothelin antagonist; The norepinephrine precursor; Anxiolytic medicament is such as stable, alprazolam, zeisin and chlorine nitrogen

Serotonin 5HT ₂Receptor antagonist; Opiates agonist such as morphine monomethyl ether, hydrocodone, U-26225A, Doloxenel and febtanyl; MGluR5 agonist, antagonist or synergistic agent; GABA A receptor modulators, for example calcium bisacetyl homotaurine; Nicotinic antagonists or agonist comprise nicotine; Muscarinic agonist or antagonist; Selective serotonin reuptake inhibitor is such as fluoxetine, paroxetine, Sertraline, duloxetine, escitalopram or citalopram; Thymoleptic are such as amitriptyline, nortriptyline, clomipramine, imipramine, Venlafaxine, P-3693A, protriptyline, Desipramine, Trimipramine or imipramine; Leukotriene antagonist is such as Singulair or Zafirlukast; Oxynitride inhibitor or oxynitride synthetic inhibitor.

The compounds of this invention can also with following drug combination: the gap is connected inhibitor; Neuron calcium channel blocker such as civamide; AMPA/KA antagonist such as LY293558; The sigma-receptor agonist; And vitamins B ₂

Moreover, the compounds of this invention can also with following drug combination: the Ergot alkaloids except Ergotamine and dihydroergotamine, such as ergotocine, ergotocine, methylergobasine, metergoline, dihydroergotoxine methanesulfonate, DHO180, dihydroergocristine, dihydroergo cryptine(DCS90) alkali, dihydro-bromocriptine parlodel alkali, dihydro-β-ergokryptine, ergotoxine, ergocornine, ergocristine, ergokryptine, bromocriptine parlodel alkali, β-ergokryptine, ergosine, ergostane, bromocriptine or methysergide.

In addition, the compounds of this invention can also with following drug combination: beta-adrenaline antagonist such as timolol, Proprasylyte, Ah Ti Lip river youngster, metoprolol or nadolol etc.; The MAO inhibitor is such as Phenelzine; Calcium channel blocker is such as flunarizine, sulphur nitrogen

Ketone, amlodipine, felodipine, nisoldipine, Isrodipine, nimodipine, lomerizine, Verapamilum, nifedipine or prochlorperazine; Nerous sedative is such as olanzapine, droperidol, prochlorperazine, chlorpromazine and Quetiapine; Anticonvulsive drug is such as topiramate, zonisamide, tonabersat, carabersat, Levetiracetam, lamotrigine, tiagabine, gabapentin, lyrica or Sodium hydrogen divalproate; Hypotensive agent, for example angiotensin-ii antagonist such as losartan, irbesartan, valsartan, Eprosartan, telmisartan, Olmesartan, medoxomil, Candesartan and candesartan cilexetil, angiotensin I antagonist, angiotensin-convertion enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, Ramipril and Trolapril; Perhaps A or MYOBLOC.

The compounds of this invention can also with following drug combination: synergistic agent, for example caffeine, H2-antagonist, dimethyl silicone oil, aluminium hydroxide or magnesium hydroxide; Separate congested agent, such as xylometazoline, suprarenin, naphazoline, fourth card azoles quinoline, propylhexedrine or left-handed Desoxyephedrine; Antitussive is such as caramiphen, pentoxyverine or Dextromethorphane Hbr; Diuretic(s); Prokinetic medicine such as Reglan or domperidone; Calmness or non-sedating antihistaminic agent, that is quick, doxylamine, Loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, Pyrilamine, terfenadine, triprolidine, synephrine, Phenylpropanolamine or pseudoephedrine such as acrivastine, Zadin, Bromazine, Parabromdylamine, carbinoxamine, chlorphenamine, chlorine Ma Siting, dextrorotation Parabromdylamine, dexchlorpheniramine, hexichol.The compounds of this invention also can with the antiemetic coupling.

In the particularly preferred embodiment, the compounds of this invention and following drug combination: antimigraine drug, such as Ergotamine or dihydroergotamine; 5-HT ₁Agonist, particularly 5-HT _1B/1DAgonist, especially sumatriptan, naratriptan, Zomitriptan, according to drawing Qu Tan, almotriptan, fluorine to cut down the general Qu Tan of Pu Tan, Donitriptan, avitriptan and Leeza, and other serotonin agonists; And cyclooxygenase-2 inhibitors, such as the selectivity COX-2 inhibitors, especially rofecoxib, L-791456, celecoxib, valdecoxib or paracoxib.

Above-mentioned Combined Preparation not only comprises the compounds of this invention and a kind of other active compound associatings, also comprises and two or more other active compound associatings.Equally, the compounds of this invention can with other drug unite for prevent, treat, control, improve or alleviate the compounds of this invention for disease or indication or its danger used.This class other drug can be used with its usual amounts and the compounds of this invention simultaneously or sequentially by its approach commonly used.When the compounds of this invention and one or more other drugs used simultaneously, pharmaceutical composition also preferably comprised other drug except comprising the compounds of this invention.Therefore pharmaceutical composition of the present invention comprises except comprising the compounds of this invention, also comprises those of one or more other active ingredients.

The weight ratio of the compounds of this invention and other active ingredients can change to some extent, and it depends on the effective dose of each composition.Usually, use the various active ingredients of significant quantity.Therefore, for example when the compounds of this invention and another kind of drug combination, the weight ratio of the compounds of this invention and this another kind medicine usually about 1000: 1 to about 1: 1000 scope, perhaps at about 200: 1 to about 1: 200 scope.The associating of the compounds of this invention and other active ingredients also usually can be in above-mentioned scope, but in all cases, should use the various active ingredients of effective dose.

In this class associating, the compounds of this invention can separate or Combined Preparation with other active medicines.And a kind of medicine can be before one or more other drug administrations, simultaneously or subsequently by identical or different administration.

The compounds of this invention can be by oral, non-stomach and intestine approach (such as intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), by sucking spraying, intranasal, vagina, rectum, hypogloeeis or topical administration, can be separately or be mixed with together the optimal dose unit form that comprises the conventional nontoxic pharmaceutically acceptable carrier, assistant agent and the vehicle that are suitable for various route of administration.Except being used for the treatment of warm-blooded animal, the compounds of this invention also can be effective to the mankind.

The pharmaceutical composition that is used for the administration the compounds of this invention can be unit dosage form easily, and can be prepared by the known any method of pharmaceutical field.All methods all comprise with active ingredient with by the carrier-bound step of one or more complementary compositions.Usually, pharmaceutical composition is by with active ingredient and liquid vehicle or thin fine solid carrier, and perhaps two kinds of carriers together evenly and closely combination if necessary, then make product be shaped to required preparation.Comprise the active compound that lysis or symptom is enough to produce required effect amount in the pharmaceutical composition.Term used herein " composition " is intended to comprise that term used herein " composition " is intended to comprise the product of the specific composition of specified quantitative, and any product that is directly or indirectly obtained by the combination of the specific composition of specified quantitative.

The pharmaceutical composition that comprises active ingredient can be to be fit to oral form, but for example tablet, lozenge troches, lozenge, water-based or oil-based suspension dispersed powders or granule, emulsion, solution, soft capsule or hard capsule or syrup or elixir.Being used for oral composition can be prepared according to the means known in the art of pharmaceutical compositions, for providing pharmacy first-class and agreeable to the taste preparation, this based composition can comprise one or more and be selected from following material: sweeting agent, perfume compound, tinting material and sanitas.The nontoxic pharmaceutically acceptable perfume compound that is suitable for preparing tablet that tablet comprises active ingredient and mixes with it.These perfume compound can be, for example inert diluent such as calcium carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent are such as starch, gelatin or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum.Tablet can be not dressing or they can postpone disintegration and absorption in gi tract by the known technology dressing, the slow releasing function of long period is provided thus.For example, the time-delay material can use such as Zerol or Stearic diglyceride.They also can pass through US Patent No. 4,256,108; 4,166,452; With 4,265, the technology of describing in 874 is carried out dressing, forms the osmosis type treatment sheet of controlled release.Oral tablet also can be mixed with to provide immediately and discharge, such as Flashmelt sheet or crisp fritter sheet, and instant or instant film.

Preparations for oral administration also can be the hard gelatin capsule form, and wherein active ingredient is and inert solid diluent, mixes such as calcium carbonate, calcium phosphate or kaolin; Perhaps be the soft gelatin capsule form, wherein active ingredient is and water or oil medium, such as peanut oil, whiteruss or mixed with olive oil.

The vehicle that is suitable for preparing aqueous suspension that aqueous suspension comprises active substance and mixes with it.This class vehicle is suspending agent, such as Xylo-Mucine, methylcellulose gum, HPMC, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, such as Yelkin TTS, the perhaps condensation product of alkylene oxide and lipid acid, such as polyoxyethylene stearic acid ester, the perhaps condensation product of oxyethane and long chain aliphatic alcohol, such as 17 oxygen ethene hexadecanols (heptadecaethyleneoxycetanol), the perhaps condensation product of oxyethane and lipid acid and the hexitol part ester of deriving, such as octadecanoic acid ester of polyethylene glycol, the perhaps condensation product of oxyethane and lipid acid and hexitan (hexitol anhydrides) the part ester of deriving is such as the polyethylene polyoxyethylene-sorbitan mono-oleate.Aqueous suspension also can comprise ethyl ester or n-propyl, one or more tinting materials, one or more perfume compound and one or more sweeting agents such as sucrose or the asccharin of one or more sanitass such as P-hydroxybenzoic acid.

Oil-based suspension can be by being suspended in vegetables oil with active ingredient, for example in peanut oil, sweet oil, sesame oil or the Oleum Cocois; Perhaps it is suspended in mineral oil, as preparing in the whiteruss.Oil-based suspension can comprise thickening material, such as beeswax, paraffinum durum or hexadecanol.Also can add sweeting agent as the aforementioned those and perfume compound so that agreeable to the taste oral preparations to be provided.These compositions can be undertaken anticorrosion by adding oxidation inhibitor such as xitix.

But be suitable for preparing the dispersed powders of aqueous suspension or dispersion agent or wetting agent, suspending agent and one or more sanitass that granule comprises active ingredient and mixes with it by adding entry.The dispersion agent or the wetting agent that are fit to can exemplify above-mentioned those that mentioned.The vehicle that can also have other is such as sweeting agent, perfume compound and tinting material.

Pharmaceutical composition of the present invention can also be O/w emulsion.Oil phase can be for example sweet oil or peanut oil of vegetables oil, perhaps mineral oil such as whiteruss or these mixture.The emulsifying agent that is fit to can be, for example gum arabic or tragacanth gum, naturally occurring phosphatide such as soybean, Yelkin TTS, and the ester of being derived by lipid acid and hexitan or part ester for example condensation product such as the polyoxyethylene sorbitan monooleate of polyoxyethylene-sorbitan mono-oleate and described part ester and oxyethane.Emulsion can also contain sweeting agent and perfume compound.

Syrup and elixir can be prepared with sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose.This class preparation can also comprise negative catalyst, sanitas and perfume compound and tinting material.

Pharmaceutical composition can be aseptic injectable water-based or oil-based suspension form.This suspension can be prepared according to those above-mentioned suitable dispersion agents of mentioning of utilization known in the art or wetting agent and suspending agent.Aseptic injection also can be nontoxic thinner or the aseptic parenteral solution in the solvent or the suspension that can non-stomach and intestine uses, and for example is the solution of 1,3 butylene glycol.In acceptable medium and solvent, spendable is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil also is commonly used for solvent or suspension medium.For this reason, can use the fixed oil of any brand, comprise synthetic list-or two-glyceryl ester.In addition, also can use lipid acid such as oleic acid in the injection.

The compounds of this invention can also be used for the rectal administration medicine with suppository form.These compositions can be by being mixed with medicine and the non-irritating excipient that is fit to, and described vehicle is solid at normal temperatures, but be liquid in rectal temperature, therefore discharges medicine in the rectum melting.This class material is theobroma oil and polyoxyethylene glycol.

Use for the part, can use creme, ointment, frozen glue, solution or the suspension etc. that comprise the compounds of this invention.Similarly, transdermal patch also can be used for topical.

Pharmaceutical composition of the present invention and method can further comprise the other treatment active compound that is usually used in treating the above-mentioned pathology indication of mentioning of this paper note.

In the process of the illness for the treatment of, prevent, control, improve or alleviate need antagonism CGRP receptor active and danger thereof, the dosage level that is fit to is generally about 0.01-500mg/kg weight in patients/day, and this dosage can be taken disposable or several times.The dosage level that is fit to can be 0.01-250mg/kg/ day, about 0.05-100mg/kg/ day or about 0.1-50mg/kg/ day.In this scope, dosage can be 0.05-0.5,0.5-5 or 5-50mg/kg/ day.For oral, composition can be tablet form, it comprises 1.0-1000 milligram active ingredient, especially comprise 1.0,5.0,10.0,15.0.20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of active ingredients, this dosage is according to the symptom adjustment that is treated the patient.The compounds of this invention can or take one or twice every day with 1-4 time scheme administration every day.

Be fit to headache, migraine, partially neural headache or the other diseases for the treatment of or its when dangerous when treating, prevent, control, improve or alleviating the compounds of this invention, when the compounds of this invention can obtain the result of satisfaction during with the per daily dose once daily of about 0.1-100 mg/kg the weight of animals or minute 2-6 administration or with the slowly-releasing form administration usually.For most of large mammals, total per daily dose is about 1.0 milligrams to about 1000 milligrams, perhaps is about 1 milligram to about 50 milligrams.In 70kg adult's situation, total per daily dose is generally about 7 milligrams to about 350 milligrams.Can adjust dosage regimen so that optimum therapeutic response to be provided.

But should be appreciated that, given dose level and the administration frequency for any particular patient can change, it depends on many factors, comprises severity and the ongoing treatment of the person of being treated of the metabolic stability of activity, this compound of the specific compound of use and action time length, age, body weight, healthy state, sex, diet, administering mode and time, excretion rate, drug combination, concrete illness.

Following reaction scheme and embodiment illustrate several preparation methods of the compounds of this invention.Raw material prepares according to methods known in the art or according to the method that this paper illustrates.

The compounds of this invention can be improved one's methods according to following reaction scheme and specific embodiment or its, uses the raw material, reagent and the conventional synthetic method that obtain easily to prepare easily.In these reactions, also can utilize for the those of ordinary skill of this area itself is changing method known but that this paper is not elaborated.Be readily appreciated that the universal method of preparation and clear preparation claim compound of the present invention by following reaction scheme this area professional and technical personnel.Such as synthetic intermediate and final compound as described in the reaction scheme 1-17.

Reaction scheme

Prepare final compound by intermediate suc as formula the compound of I and formula II, and this paper describes the synthetic method of every kind of intermediate.

Generally, formula III is connected with the IV intermediate to connect by the urea shown in scheme 1 and is carried out coupling.Intermediate 1The amine that obtains behind the deprotection can be converted into the reactive amino manthanoate, such as the p-nitrophenyl carbamate 2, with its subsequently with such as intermediate 3Amine reaction, obtain urea 4Can be used for preparing compound as 4Other activated intermediates be that this area professional and technical personnel is known.For example, 1The primary amine that obtains behind the deprotection can be directly with suitable urea chloride acidylate.

Scheme 1

The synthetic of compound shown in the intermediate compound IV can be finished by the method that is similar to what follows: Henning etc., J Med.Chem., 1987,30,814-819; Carpino etc., WO96/35713; Brown etc., J Chem.Soc.1957,682-686; Barlin etc., Aust.J.Chem.1982,55 (11), 2299-2306; And the reference of wherein quoting from.

In addition, the synthetic of compound shown in the formula IV can carry out according to scheme 2-10.Diamino heterocycle for example is such as 2,3 diamino pyridine 5Available as 6Ketone carry out reductive alkylation, obtain but alkylate 7(scheme 2).Use the carbonyl dimidazoles closed loop, obtain imidazolone 8Under standard conditions, carry out last deprotection, obtain intermediate 3

Scheme 2

According to scheme 3 preparation Triazolinones.4-piperidone for example 9Available hydrazonium salt (carbazates) reduction amination, hydrazone 10After being reduced, obtain monoalkylated product 11Deprotection obtains hydrazine 12, and with benzene first sulfonyl carbamate as 13Carry out condensation/closed loop, obtain Triazolinones 14Under standard conditions, carry out last deprotection, obtain product 15

Scheme 3

Intermediate 21Can be according to (Chem.Pharm.Bull.1985,33,1116-1128) the described method preparations such as Takai of scheme 4 explanations.

Scheme 4

Shown in scheme 5, adopt similar synthesis strategy synthesis type 29Relevant benzodiazepine

Ketone.Raw alcohol 22Commercially available or according to the preparation of the known method of this area professional and technical personnel.Use standard conditions, such as triphenylphosphine and bromine with alcohol 22Transform the preparation bromide 23This halogenide is with the displacement of trinitride nucleophilic reagent, reduces trinitride under standard conditions 24Obtain primary amine 25This amine obtains compound with the 4-piperidone reduction amination of suitable protection 26Utilize multiple condition all can easily reduce nitro, use subsequently the carbonyl dimidazoles cyclization, obtain the ring-type urea 28Then deprotection disengages amine 29

Scheme 5

Quinolone 34By negatively charged ion and the piperidone that is obtained by 2-chloroquinoline and lithium diisopropylamine 31Reaction preparation (scheme 6).The Concomrnitant that uses aqueous hydrochloric acid to finish the tertiary alcohol eliminates the hydrolysis of reaction and chloroquinoline.Remove the N-benzyl protecting group of piperidines and reduce the ethylene linkage that forms in the preceding step by catalytic hydrogenation, obtain amine 34

Scheme 6

The 7-azaindole ( 35) can utilize various protecting groups, (trimethylammonium man silyl) ethoxyl methyl is protected shown in scheme 7.According to the method for Marfat and Carter (TetrahedronLett, 1987,28,4027-4030), process with hydrogen bromide pyridine perbromide (pyridine ehydrobromide perbromide) 36, obtain dibromo band azepine oxindole 37, it is reduced to corresponding azepine oxindole by the reaction with zinc 38Use cesium carbonate in DMF, to carry out 38With 1,2-two (brooethyl)-4 benzoic acid methyl esters ( 39) crucial alkylation, obtain spiral shell azepine oxindole 40Also can use various other alkali and solvents in this alkylated reaction, show to obtain different products with another kind of dibromide alkylating reagent herein.Remove the SEM protecting group under standard conditions after, saponification obtains sour intermediate 42Method shown in the scheme 7 be not limited to the azepine oxindole as 38, also can be applicable to various suitable protected heterocyclic systems, to obtain to screw togather accordingly compound.

Scheme 7

The azepine oxindole 38Use cesium carbonate in DMF, to carry out with the alkylation of suitable-Isosorbide-5-Nitrae-dichloro-2-butene, obtain spiral shell azepine oxindole 43(scheme 8).After under standard conditions, removing the SEM protecting group, by the dihydroxy reaction of perosmic anhydride catalysis, obtain two alcohol intermediates 45Decompose glycol with periodate oxidation, then carry out the reduction amination (Org.Lett, 2000,26,4205-4208), obtain spiroperidol 46Method shown in the scheme 8 be not limited to the azepine oxindole as 38, also can be applicable to various suitable protected heterocyclic systems, to obtain to screw togather accordingly compound.

Scheme 8

The synthetic of relevant spiral shell pyrido-benzoxazine ketone can be finished according to scheme 9.Under the effect of hexamethyl dimethyl silanyl sodium amide and tert-Butyl dicarbonate, with its Boc derivative form protection 2-amino-6-chloropyridine 47Under the Davies condition (Tetrahedron Lett, 2004,45,1721-1724) carry out Ortho metallization and the gained negatively charged ion is added to N-carbobenzoxy-(Cbz)-4-piperidone, obtain product after the cyclization on the spot 50Under standard conditions, carry out final deprotection and the reaction that removes chlorine, obtain intermediate 51

Scheme 9

In the scheme 10, the 4-keto piperidine 49Wittig reaction obtain alpha, beta-unsaturated esters 52.Under alkaline condition (Tetrahedron Lett, 2004,4401-4404), the products therefrom isomery is turned to beta, gamma-unsaturated ester 53Carry out the amidate action that trimethyl aluminium is medium with 2-amino-3-bromopyridine, then use 2-(TMS) oxyethyl group methyl chloride to carry out alkylation of amide, obtain product 55Crucial palladium be the volution of medium close reaction can improve one's methods by the Fu of Heck reaction (J Amer.Chem.Soc, 2001,6989-7000) carry out.Under standard conditions, follow two step deprotections of reduction, obtain spiral shell naphthyridones (spiral shell naphthyridines) 57

Scheme 10

The ethylene linkage transposition strategy of summarizing according to scheme 11 is the assembly hexanolactam again.Under the alkaline condition of gentleness, 2,4-dimethoxybenzylamine hydrochloride with the alkylation of 2,3-propylene bromide, is obtained amine 59Under various conditions, will be by the D-allyl oxyglycerol that is purchased according to currently known methods (JChem.Soc, 1962,3963-3968) (2R)-2-{[(benzyloxy of a step preparation) carbonyl] amino } penta-obtusilic acid ( 60) and amine 59Coupling obtains acid amides 61Can use the coupling of carrying out on the different transition metal-catalyzed vinyl bromide compounds, for example use the arylation of the palladium catalysis of phenyl-boron dihydroxide and yellow soda ash, obtain styrene derivatives 62In the presence of Grubbs two generations ruthenium catalyst, in methylene dichloride, carry out the closed loop transposition by mild heat, obtain lactan 63Remove dimethoxy-benzyl and the on the spot primary amine hydrogenation of protection, obtain corresponding saturated lactan 65

With Lawesson ' s agent treated, obtain general formula 66Thioamide compound.

Scheme 11

Perhaps, shown in scheme 12, can introduce the C6-aryl.Nitromethane 99Min. is added to the aldehyde of known glutamic acid derivative 67(Tetrahedron Asymmetry, 1998,3381-94) in, then eliminate on the spot and obtain nitroolefin 68Reaction through boric acid derivatives or similar equivalent addition aryl can be carried out in the stereoselectivity mode by chiral ligand-Rh catalysis.Follow the hydrolysis that nitroreduction and benzyl ester occur, obtain amino acid 70Then closed loop under standard conditions removes a tertbutyloxycarbonyl, obtains lactan 72With Lawesson ' s agent treated, obtain general formula 73Thioamide compound.

Scheme 12

But application class is introduced the variation (scheme 13) of 6 groups of hexanolactam like strategy.Use Grubbs two generations ruthenium catalyst can be in the vinyl bromide compound 61On directly carry out the closed loop transposition, obtain the ring-type bromide 74Remove dimethoxy-benzyl and use boric acid to carry out the target catalytic coupling, obtain general formula 76Compound. 75To 76Conversion be not limited to boric acid derivatives.After the standard hydrogenation, obtain general formula with Lawesson ' s agent treated 78Thioamide compound.

Scheme 13

Perhaps, Grignard or similar reagents are added to nitroolefin 68In, then by nitroreduction and benzyl ester hydrogenolysis, obtain each seed amino acid as 80(scheme 14).Then closed loop under standard conditions removes a tertbutyloxycarbonyl, obtains lactan 77Obtain general formula with Lawesson ' s agent treated 78Thioamide compound.

Scheme 14

Can be purchased or shown in scheme 15, be prepared for the synthetic essential amino alcohol of imidazoles.Process aldehyde with the cyaniding trimethyl silyl, obtain cyano group alcohol 81, with its amino alcohol that obtains suiting with the lithium aluminium hydride reduction 84

Scheme 15

Shown in scheme 16, prepare condensed imidazole.In the presence of mercury chloride (II), with thioamides 78With various amino alcohols 84Reaction obtains amidine 85Should alcohol with Dess-Martin periodinane or dichromic acid oxidation of methylpyridine, follow ring-closure reaction, finally obtain the imidazoles of general formula 1.

Scheme 16

Shown in scheme 17, prepare triazole derivative.Hydrazine is added to thioamides 78In, obtain corresponding hydrazine compound 86Under standard conditions, various carboxylic acids or acyl chlorides can carry out coupling, after the closed loop, obtain required anellated triazoles 87

Scheme 17

In some situation, final product can also further be modified for example substituent processing.These processing can include, but are not limited to usually known reduction, oxidation, alkylation, acidylate and hydrolysis reaction of those skilled in the art.And in some cases, the order of carrying out the previous reaction scheme can change, and is beneficial to the reaction product of reacting or avoiding not expecting.

Intermediate and embodiment

Provide the following example to help comprehend the present invention.These embodiment only are illustrative, should not be understood as and limit by any way the present invention.

Intermediate 1

2-oxo-1-(4-piperidyl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine disalt Hydrochlorate

Steps A .2-amino-3-tertbutyloxycarbonyl piperidin-4-yl) amino) pyridine

Under the room temperature, sodium triacetoxy borohydride (14.5g, 68.7mmol) is added to 2,3 diamino pyridine (5.00g, 45.8mmol) and the solution of (75mL) of N-(tertbutyloxycarbonyl)-4-piperidone (9.58g, 48.1mmol) in ethylene dichloride in.After 5 hours, again add other sodium triacetoxy borohydride (1.8g) and through 2.5 hours.Reactant stirred spend the night, and with 5% aqueous sodium hydroxide solution termination reaction.The reactant dichloromethane extraction is with 5% aqueous sodium hydroxide solution, water and saturated nacl aqueous solution washing.After dried over sodium sulfate, with solution filter and evaporation, obtain crude product.This product obtains title compound (4.44g) through chromatogram purification (silica gel, 3～5% methyl alcohol-dichloromethane gradient wash-out).MS?293(M+1) ¹H?NMR(500MHz，CD ₃OD)δ7.32(dd，J＝5，1Hz，1H)，6.85(dd，J-8，1Hz，1H)，6.59(dd，J＝8，5Hz，1H)，4.04(d，J＝13Hz，2H)，3.46(m，1H)，2.98(brs，2H)，2.01(dd，J＝12，2Hz，2H)，1.46(s，9H)，1.37(qd，J＝12，4Hz，2H)。

Step is oxo-1-(1-tertbutyloxycarbonyl piperidin-4-yl)-2 B.2-, 3-dihydro-1H -imidazo [4,5-b] pyridine

Under the room temperature, carbonyl dimidazoles (0.70g, 4.33mmol) is added to 2-amino-3-[(1-tertbutyloxycarbonyl piperidin-4-yl) amino] in the solution of pyridine (1.15g, 3.93mmol) in acetonitrile (150mL).After a few hours, add other carbonyl dimidazoles (0.81g), and the reactant stirring is spent the night.Vacuum-evaporation acetonitrile, resistates are assigned in water and the chloroform, and organic phase with saturated derive the washing and through dried over mgso.Crude product obtains title compound (1.09g) through chromatogram purification (silica gel, 1.2～2.5% methyl alcohol-dichloromethane gradient wash-out). ¹H?NMR(500MHz，CDCl ₃)δ9.39(br?s，1H)，8.04(dd，J＝5，1Hz，1H)，7.33(dd，J＝8，1Hz，1H)，6.99(dd，J＝8，5Hz，1H)，4.50(m，1H)，4.32(br?s，2H)，2.86(br?s，2H)，2.20(m，2H)，1.86(d，J＝12Hz，2H)，1.50(s，9H)。

Step is oxo-1-(4-piperidyl)-2 C.2-, 3-dihydro-1H-imidazo [4,5-b] The pyridine dihydrochloride

Under the room temperature, with 2-oxo-1-(1-tertbutyloxycarbonyl piperidin-4-yl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine (1.03g, 3.23mmol) is dissolved in the methyl alcohol (25mL) and adds 2N salt acid ether (8mL) solution.After 2 hours, vacuum is removed volatile matter, obtains title compound (0.92g).MS?219(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ8.01(dd，J＝6，1Hz，1H)，7.83(d，J＝8Hz，1H)，7.28(dd，J＝8，6Hz5?IH)，4.60(m，1H)，3.59(d，J＝12Hz，2H)，3.21(t，J＝12Hz，2H)，2.70(dq，J＝13，4Hz，2H)，2.12(d，J＝13Hz，2H)。

Intermediate 2

4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1 -formyl chloride

Under 0 ℃, with phosgene (20%wt toluene solution; 1.8mL, 3.43mmol) be added to 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-dichloride (100mg, 0.343mmol) and methylene dichloride (5mL) suspension of 2,6-lutidine (0.50mL, 4.293mmol) in.After 2 hours, be added to this solution in the saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.Organic layer water (2x), saturated brine washing through dried over mgso, are filtered and are concentrated.Add methylene dichloride (10mL), filtering mixt obtains the title compound (48mg) of solid.MS?281(M+1)。 ¹H?NMR(500MHz，(CD ₃) ₂SO)δ11.58(s，1H)，7.90(d，J＝5.1Hz，1H)，7.67(d，J＝7.6Hz，1H)，7.01-6.99(m，1H)，4.52-4.46(m，1H)，4.31-4.23(m，2H)，3.38-3.33(m，1H)，3.19-3.14(m，1H)，2.32-2.24(m，2H)，1.84-1.81(m，2H)。

Intermediate 3

7-piperidin-4-yl-7,9-dihydro-8H-purine-8-keto hydrochloride

Steps A .4-amino-5-[(1-tertbutyloxycarbonyl piperidin-4-yl) amino) pyrimidine

With 4,5-di-amino-pyrimidine (1.0g, 9.1mmol), N-(tertbutyloxycarbonyl)-4-piperidone (3.0g, 15mmol) and the mixture of sodium triacetoxy borohydride (1.2g, 5.6mmol) in ethylene dichloride (60mL) stirring at room 3 days.Reactant distribution is arrived in chloroform (200mL) and the 3N sodium hydroxide (30mL).After dried over mgso, organic phase is concentrated, obtains the title compound of brown glue.MS?294(M+1)

Step is (1-benzyl piepridine-4-yl)-7 B.7-, 9-dihydro-8H-purine-8-ketone

The crude product 4-amino that steps A is obtained-5-[(1-tertbutyloxycarbonyl piperidin-4-yl) amino) pyrimidine and carbonyl dimidazoles (3.0g, 18mmol) refluxed 2 days in tetrahydrofuran (THF) (250mL), and cooling is also concentrated.Crude product is dissolved in ethyl acetate, and (25～50mL), quadruplication obtains the title compound (1.3g) of white crystalline solid.MS?320(M+1)

Step is piperidin-4-yl-7 C.7-, 9-dihydro-8H-purine-8-keto hydrochloride

With 7-(1-benzyl piepridine-4-yl)-7, the 9-dihydro-mixture of 8H-purine-8-ketone (1.2g, 3.7mmol) in 4N hydrogenchloride De diox (50mL) was room temperature vigorous stirring 3 hours.With the reactant vacuum concentration, obtain the title compound of white solid.MS?220(M+1)

Intermediate 4

4-fluoro-2-oxo-1-(4-piperidyl)-2,3-dihydro-1H-imidazo [4,5-b] Pyridine

Steps A .N-(5-fluorine pyridine-2-yl)-2,2-dimethyl propylene acid amides

2-amino-5-fluorine pyridine (1.00g toward 0 ℃, 8.92mmol) and triethylamine (1.35g, 13.4mmol) add trimethyl-acetyl chloride (1.29g, 10.7mmol) and DMAP (0.11g, 0.89mmol) in the solution in methylene dichloride (30mL).Make this solution be warming to room temperature.After 4 hours, add saturated sodium bicarbonate aqueous solution, the solution layering is also washed water with the DCM backwash.The organic phase that merges is through dried over mgso, filtration and concentrated, and resistates obtains title compound (1.34g) through silica gel chromatography purifying (5% → 40%EtOAc/ hexane).MS?197.3(M+1)。 Step B.N-(3-azido--5-fluorine pyridine-2-yl)-2,2-dimethyl propylene acid amides

Past-78 ℃ N-(5-fluorine pyridine-2-yl)-2, drip in the tetrahydrofuran (THF) of 2-dimethyl propylene acid amides (1.34g, 6.83mmol) (25mL) solution tert-butyl lithium (1.31mL 1.7M solution, 20.5mmol).-78 ℃ through after 3 hours, be added to 4-dodecylbenzene sulfuryl azide (3.60g, 10.2mmol) in the reactant and make it be warming to room temperature.After 1 hour, add saturated aqueous ammonium chloride, remove tetrahydrofuran (THF) through rotatory evaporator.Add methylene dichloride, layering is also washed water with the DMC backwash.Through dried over mgso, filtration and concentrated, resistates obtains title compound (0.275g) through twice order silica gel chromatography purifying (10% → 80%EtOAc/ hexane, then 5% → 42%EtOAc/ hexane) with the organic phase that merges.MS?234.0(M+1)。

Step is azido--5-fluorine pyridine-2-amine C.3-

With N-(3-azido--5-fluorine pyridine-2-yl)-2,2-dimethyl propylene acid amides (275mg, 1.16mmol) is heated to 100 ℃ in 3N HCl (5mL).After 2 hours, vacuum is removed volatile matter, obtains the title compound (180mg) of its hydrochloride form.MS?154.2(M+1)。

Step is fluorine pyridine-2 D.5-, the 3-diamines

The hydrochloride of 3-azido--5-fluorine pyridine-2-amine (1.90g, 10.0mmol) is dissolved in tetrahydrofuran (THF) (100mL) and uses MP-carbonic ether (Argonaut, 11.5g) to process.After 1 hour, this mixture is filtered, using more, the tetrahydrofuran (THF) of volume washes and is concentrated.This resistates is dissolved in ethanol (50mL), with argon purge and add 10% palladium charcoal (0.15g).Introduce hydrogen (1 normal atmosphere) and stirring reaction is extremely complete.Filtration catalizer, the filtrate evaporating solvent obtains title compound (1.18g).MS?128.0(M+1)

Step e .4-[(2-amino-5-fluorine pyridin-3-yl) amino] piperidines-1-formic acid uncle fourth Ester

Under the room temperature, with sodium triacetoxy borohydride (2.95g, 13.9mmol) be added to 5-fluorine pyridine-2,3-diamines (1.18g, 9.28mmol), acetic acid (0.56g, 9.28mmol) and 1-(tertbutyloxycarbonyl)-4-piperidone (1.85g, 9.28mmol) in the solution of 1,2-ethylene dichloride (20mL).After 1 hour, will react water (20mL) and stop and use dichloromethane extraction.Only after the dried over sodium sulfate, with solution filter and evaporation, obtain crude product.Product is through chromatogram purification (silica gel, 5% → 15%MeOH/DCM; Then C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (0.73g).MS?311.2(M+1)。

Step F .4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine -1-yl) piperidines-1-t-butyl formate

Under the room temperature, carbonyl dimidazoles (1.53g, 9.41mmol) is added to 4-[(2-amino-5-fluorine pyridin-3-yl) amino] in the solution of piperidines-1-t-butyl formate (0.73g, 2.35mmol) in acetonitrile (10mL).Reaction stirred is until whole raw material exhausts (about 2 hours), then vacuum evaporating solvent.Resistates washes with water, with dichloromethane extraction (3x), through dried over mgso and concentrated.Crude product obtains title compound (0.309g) through chromatogram purification (silica gel, 1%～10% methyl alcohol-dichloromethane gradient wash-out).MS?337.2(M+1)

Step is fluoro-2-oxo-1-(4-piperidyl)-2 G.4-, 3-dihydro-1H-imidazo [4,5-b] pyridine

4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo [4,5-5] pyridine-1-yl) piperidines-1-t-butyl formate (340mg, 1.01mmol) is dissolved in methylene dichloride (5mL) and adds trifluoroacetic acid (5mL).After 2 hours, reactant is concentrated, dilute with methylene dichloride (5mL), and at room temperature add Isosorbide-5-Nitrae-dioxs (2mL) solution of 1N hydrochloric acid.The concentrated title compound (302mg) that obtains.MS?237.2(M+1) ¹H?NMR(500MHz，CD ₃OD)δ7.92(br?s，1H)，7.70(dd，1H)，4.60(m，1H)，3.60(s，2H)，3.25(dd，2H)，2.70(m，2H)，2.10(d，2H)。

Intermediate 5

3-(4-piperidyl)-3,4-dihydroquinazoline-2 (1H)-keto hydrochloride

The method of describing in Chem.Pharm.Bulletin 1985,33 (3) 1116-1128 according to H.Takai etc. prepares title compound. ¹H?NMR(500MHz，DMSO-d ₆)δ9.31(s，1H)，8.79(br?s，1H)，8.58(br?s，1H)，7.13(t，J-8Hz，2H)，6.88(t，J＝8Hz，1H)，6.77(d，J＝8Hz，1H)，4.37(tt，J＝12，4Hz，1H)，4.29(s，2H)，3.00(q，J＝11Hz，2H)，2.06(dq，J＝4，12Hz，2H)31.73(d，J＝12Hz，2H)。

Intermediate 6

5-phenyl-1-piperidin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-ketone salt Hydrochlorate

Steps A: 9H-fluorenes-9-ylmethyl 4-[(tertbutyloxycarbonyl) hydrazono-] piperidines-1-first Acid esters

With 1-[(9H-fluorenes-9-yl) methoxycarbonyl]-4-piperidone (16.0g, 50.0mmol) and tert-butyl carbazate (7.25g, the 55.5mmol) solution in ethanol (250mL) refluxed 1 hour.With solution cooling and concentrated.Add the rear title compound (21.0g) that produces white precipitate of ether (100mL). ¹H?NMR(500MHz，CDCl ₃)δ7.77(d，J＝7Hz，2H)，7.57(d，J＝7Hz，2H)，7.40(t，J＝7Hz，2H)，7.32(t，J＝7Hz，2H)，4.50(br?s，2H)，4.24(t，J＝6Hz，1H)，3.4-3.7(br?m，4H)，2.47(br?s，2H)，2.2-2.1(br?m，2H)，1.56(s，9H)。

Step B:9H-fluorenes-9-ylmethyl 4-[(tertbutyloxycarbonyl) diazanyl] piperidines-1-formic acid Ester

In the Pa Er device, with 9H-fluorenes-9-ylmethyl 4-[(tertbutyloxycarbonyl) hydrazono-] acetic acid (150mL) solution of piperidines-1-manthanoate (10.0g, 22.9mmol) is with platinum oxide (1.0g) jolting 2 hours under 45psi hydrogen.Filter this solution and concentrated, obtain title compound.

Step C:9H-fluorenes-9-ylmethyl 4-diazanyl piperidines-1-manthanoate

With 9H-fluorenes-9-ylmethyl 4-[(tertbutyloxycarbonyl) diazanyl] piperidines-1-manthanoate (20g, 45.7mmol) is dissolved in trifluoroacetic acid (100mL) and stirring at room 1.5 hours.Reactant is concentrated and resistates is dissolved in methyl alcohol, through the reversed-phase HPLC purifying.Separate pure cut and merging, obtain the trifluoroacetate (3.01g) of title compound. ¹H?NMR(500MHz，DMSO-d ₆)δ7.89(d，J＝8Hz，2H)，7.61(d，J＝8Hz，2H)，7.40(t，J＝8Hz，2H)，7.32(t，J＝8Hz，2H)，4.33(d，J＝6Hz，2H)，4.25(t，J＝6Hz，1H)，4.0-3.5(br?s，6H)，3.05(br?s，1H)，2.80(br?s，2H)，1.89(br?s，2H)，1.2(br?s，2H)。

Step D:9H-fluorenes-9-ylmethyl 4-(5-oxo-3-phenyl-4, the 5-dihydro- 1H-1,2,4-triazol-1-yl) piperidines-1-manthanoate

With 9H-fluorenes-9-ylmethyl 4-diazanyl piperidines-1-manthanoate trifluoroacetate (2.95g, 6.54mmol) and N-benzene first sulfonyl carbamate (1.50g, 7.1mmol) (pass through E.P.Papadopoulus, J Org.Chem., 1976, the preparation of 41 (6) 962-965 methods) in the tetrahydrofuran (THF) that contains diisopropyl ethyl amine (1.25mL, 7.1mmol) (30mL) solution, refluxed 2 hours.With reactant cooling and concentrated, then heating for dissolving in acetonitrile.Through cooling adularescent solid crystal, obtain title compound (2.06g). ¹H?NMR(500MHz，CDCl ₃)δ7.80(d，J＝7Hz，2H)，7.77(d，J＝7Hz，2H)，7.61(d，J＝7Hz，2H)，7.48(m，3H)，7.40(t，J＝7Hz，2H)，7.33(t，J＝7Hz，2H)，4.46(d，J＝6Hz，2H)，4.36(m，2H)，4.27(t，J＝6Hz，1H)，4.26(br?s，1H)，3.02(br?s，2H)，2.04(br?s，2H)，1.94(br?m，2H)。

Step e: 5-phenyl-1-piperidin-4-yl-2,4-dihydro-3H-1,2,4-triazole- The 3-keto hydrochloride

With 9H-fluorenes-9-ylmethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl) tetrahydrofuran (THF) (15mL) solution of piperidines-1-manthanoate (2.06g, 4.41mmol) and diethylamine (15mL) was stirring at room 2 hours.Reactant is concentrated, and crude product obtains the title compound (0.95g) of white solid through column chromatography purifying (silica gel, 0～10%{5% ammonium hydroxide/methyl alcohol } dichloromethane solution gradient elution). ¹H?NMR(500MHz，CDCl ₃)δ7.84(d，J＝7Hz，2H)，7.47(m，3H)，4.30(m，1H)，3.25(d，J＝13Hz，2H)，2.79(t，J＝13Hz，2H)，2.04(d，J＝4，12Hz，2H)，1.93(br?d，J＝10Hz，2H)。

Intermediate 7

3-(4-piperidyl)-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine

-2-keto hydrochloride

Steps A .2-(2-bromotrifluoromethane) oil of mirbane

Under 0 ℃, triphenylphosphine (39.2g, 0.150mol) and carbon tetrabromide (49.5g, 0.150mol) order are added in methylene dichloride (400mL) solution of 2-(2-hydroxyethyl)-oil of mirbane (25.0g, 0.150mol).To react to stir and spend the night and use the saturated sodium bicarbonate aqueous solution termination reaction.Methylene dichloride is with the saturated brine washing and through dried over mgso.Crude product is processed with ethyl acetate, and removes by filter the triphenylphosphine oxide of precipitation.Be further purified (silica gel, the hexane solution gradient elution of 0～10% ethyl acetate) through flash chromatography, obtain title compound (27.9g).

Step is (2-azido-ethyl) oil of mirbane B.2-

With the sodiumazide in the water (60mL) (22.8,0.351mol) be added in acetonitrile (120mL) solution of 2-(2-bromotrifluoromethane)-oil of mirbane (27.9g, 0.121mol).Reactant was refluxed 4 hours, cool off and be assigned in methylene dichloride and the water.Organic phase is with the saturated brine washing and through dried over mgso.Obtain the title compound (22.8g) of oily.

Step is (2-amino-ethyl) oil of mirbane C.2-

Triphenylphosphine (31.1g, 0.118mol) and calcium carbonate (50mg, 0.5mmol) are added in the solution of benzene (500mL) of 2-(2-azido-ethyl) oil of mirbane (22.8g, 0.118mol).To react in stirring at room to abundant.Solvent removed in vacuo, resistates was processed 1 hour under 100 ℃ with acetic acid (100mL) and 48% hydrogen bromide (100mL).With reactant cooling and concentrated.Add entry, the solution dichloromethane extraction.Make water layer be alkalescence by adding 5% aqueous sodium hydroxide solution, then use ethyl acetate extraction.Organic phase is with the saturated brine washing and through dried over sodium sulfate.Obtain the title compound (8.0g) of oily.MS?167(M+1)。

Step is (2-nitrophenyl) ethyl D.4-{[2-] amino } piperidines-1-t-butyl formate

Add acetic acid, make methyl alcohol (100mL) solution of 2-(2-amino-ethyl) oil of mirbane (8.00g, 48.1mmol) and 1-tertbutyloxycarbonyl-4-piperidone (9.59g, 48.1mmol) reach pH 5.Add sodium cyanoborohydride (4.53g, 72.2mmol) and will react stirring 3 hours.Vacuum is removed methyl alcohol, and resistates is assigned in ethyl acetate and the saturated sodium bicarbonate solution.Organic phase is with the saturated brine washing and through dried over sodium sulfate.Obtain the title compound (19.27g) of oily.MS350(M+1)。

Step e .4-{[2-(2-aminophenyl) ethyl] amino } piperidines-1-t-butyl formate

Under an atmospheric nitrogen atmosphere, with 4-{[2-(2-nitrophenyl) ethyl] amino } piperidines-1-t-butyl formate and 10% palladium charcoal (1.9g) stir in ethanol (250mL) and spend the night.From the solution filtration catalizer, solvent removed in vacuo must be marked title compound (17.2g).MS320(M+1)

Step F .3-(1-tertbutyloxycarbonyl-4-piperidyl)-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine

-2-ketone

Carbonyl dimidazoles (8.73g, 53.8mmol) is added to 4-{[2-(2-aminophenyl) ethyl] amino } in dimethyl formamide (200mL) solution of piperidines-1-t-butyl formate (17.2g, 53.8mmol) and stirring at room 2 hours.Then reactant extracts with saturated brine with ethyl acetate dilution and water extraction.Crude product is through chromatogram purification (silica gel, 0～30% ethyl acetate in dichloromethane gradient wash-out).Obtain the title compound (4.8g) of dark-coloured solid.

Step is (4-piperidyl)-1,3,4 G.3-, 5-tetrahydrochysene-2H-1,3-benzodiazepine

-2-keto hydrochloride

Under 0 ℃, with 3-(1-tertbutyloxycarbonyl-4-piperidyl)-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine

The ethyl acetate of-2-ketone (4.80g, 13.9mmol) (300mL) solution is saturated with hydrogenchloride.The time reactant be warming to room temperature and stir and spend the night.Wash with solid filtering and with ethyl acetate.The concentrated second batch product that obtains of ethyl acetate filtrate.Obtain the title compound (2.94g) of solid.MS?246(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ7.10(m，2H)，6.94(d，J＝8Hz5?1H)，6.91(t，J＝8Hz，1H)，4.35(tt，J＝10，1Hz，1H)，3.52(m，4H)，3.12(t，J＝12Hz，2H)33.05(m，2H)，2.07(qd，J＝12，4Hz，2H)，1.99(m，2H)。

Intermediate 8

3-(4-piperidyl) quinoline-2-(1H)-ketone

Steps A .3-f1-benzyl-4-hydroxy piperidine-4-yl)-the 2-chloroquinoline

Under-78 ℃ and argon atmospher, the hexane solution (1.6M, 38.2mL, 61.1mmol) of n-Butyl Lithium is added in tetrahydrofuran (THF) (140mL) solution of diisopropyl ethyl amine (8.6mL, 61.1mmol).After 1 hour, add tetrahydrofuran (THF) (30mL) solution of 2-chloroquinoline (10.00g, 61.1mol) through syringe.After 1 hour, add 1-benzyl-4-piperidone (11.3mL, 61.1mmol) solution, and after 40 minutes, make it be warming to room temperature in-78 ℃ of restir reactant.Reaction is cooled to-20 ℃ and water termination reaction.The reaction soln ethyl acetate extraction, organic phase is with the saturated brine washing and through dried over mgso.Through chromatogram purification (silica gel, 0～10%{5% ammonium hydroxide/methyl alcohol } dichloromethane gradient wash-out), obtain title compound, 11.3g.MS?353(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ8.33(s，1H)，8.00(d，J＝8Hz，1H)，7.82(d，J＝8Hz，1H)，7.72(dt，J＝1，10Hz，1H)，7.57(dt，J＝1，8Hz，1H)，7.39-7.26(m，5H)，3.61(s，2H)，2.85(d，J＝11Hz，2H)，2.59(t，J＝12Hz，2H)，2.48(dt，J＝4，13Hz，2H)，2.13(d，J＝12Hz，2H)。

Step is (1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) quinoline-2-(1H)-ketone B.3-

3-(1-benzyl-4-hydroxy piperidine-4-yl)-2-chloroquinoline (11.0g, 31.1mmol) was refluxed 8 hours in 6N hydrochloric acid.With solution cooling and add entry (100mL).The solid of collecting precipitation is also dry, obtains title compound, 7.9g.MS?317(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ7.97(s，1H)，7.70(d，J＝7Hz，1H)，7.60(m，2H)，7.55(m，4H)，7.35(d，J＝9Hz，1H)，7.27(t，J＝8Hz，1H)，6.50(m，1H)，4.49(ABq，J＝13Hz，Δv＝16Hz，2H)，3.92(m，2H)，3.76(dt，J＝12，4Hz，1H)，3.40(m，1H)，2.96(m，2H)。

Step is (4-piperidyl) quinoline-2-(1H)-ketone C.3-

Methyl alcohol (500mL) solution argon-degassed with 3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) quinoline-2-(1H)-ketone (4.00g, 12.6mmol) adds 10% palladium charcoal (1.2g).Reactant placed under the hydrogen-pressure and in 50 ℃ of heating 5.5 hours.With reactant cooling and filtration over celite.The concentrated title compound, 2.7g of obtaining.MS?229(M+1)。 ¹HNMR (500MHz, CD ₃OD) δ 7.80 (s, 1H), 7.67 (d, J=8Hz, 1H), 7.51 (t, J=8Hz, 1H), 7.33 (d, J=8Hz, 1H), (7.25 t, J=8Hz, 1H), 3.52 (t, J=12Hz, 2H), 3.17 (dt, J=3,13Hz, 2H), 3.15 (m, with the peak overlapping of δ 3.17,1H), 2.18 (d, J=14Hz, 2H), 1.91 (dq, J=3,12Hz, 2H).

Intermediate 9

1-piperidin-4-yl imidazolidine-2,4-dione

Steps A: 4-[(2-oxyethyl group-2-oxo-imidazole alkane-1-yl) piperidines-1-formic acid uncle fourth Ester

Sodium cyanoborohydride (189mg, 3.01mmol) is added in methyl alcohol (12.5mL) solution of 1-boc-4-piperidone (500mg, 2.51mmol) and glycine ethyl ester hydrochloride (350mg, 2.51mmol).After 16 hours, make reaction terminating with saturated ammonium chloride solution, concentrate and be assigned in methylene dichloride and the saturated sodium bicarbonate solution.Organic layer filters and concentrates with the salt water washing, through dried over mgso.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/5% (10% ammonium hydroxide/methyl alcohol)], obtain title compound (600mg).

Step B:4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-t-butyl formate

Cyanic acid first (31mg, 0.384mmol) is added to 4-[(2-oxyethyl group-2-oxygen ethyl) amino] in water (2mL) solution of piperidines-1-t-butyl formate (100mg, 0.384mmol).Then add that acetic acid transfers to 4-5 with reactant pH and with mixture in 40 ℃ of heating.After 16 hours, with the reactant cool to room temperature and through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (33mg).

Step C:1-piperidin-4-yl imidazolidine-2,4-dione

Trifluoroacetic acid (0.300mL) is added in methylene dichloride (1mL) solution of 4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-t-butyl formate (32mg, 0.113mmol).After 4 hours, reactant is concentrated, obtain title compound.MS?184.04(M+1)。

Intermediate 10

(±)-2 '-oxo-1,1 ', 2 ', 3-tetrahydrochysene spiral shell [indenes-2,3 '-pyrrolo-[2,3-b] pyridine]-5 -formic acid

Steps A .1-{[2-TMS) oxyethyl group] methyl }-1H-pyrrolo-[2,3-b] Pyridine

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 16.2g, 0.404mol) be added in DMF (200mL) solution of 7-azaindole (39.8g, 0.337mol) and with this mixture through gradation in 25 minutes and stirred 1 hour.Then added lentamente 2-(TMS) oxyethyl group methyl chloride (71.8mL, 0.404mol) through 15 minutes, make the temperature of reaction mixture keep below 10 ℃.After 1 hour, reaction water (500mL) stop and with mixture with dichloromethane extraction (5x300mL).The organic layer salt water washing that merges is through MgSO ₄Drying is filtered, and is concentrated and dry under high vacuum, obtains title compound.MS：m/z＝249(M+1)。

Step B.3,3-two bromo-1-{[2-(TMS) oxyethyl groups] methyl-1,3-two Hydrogen-2H-pyrrolo-[2,3-b] pyridin-2-ones

Through 30 minutes, with 1-{[2-(TMS) oxyethyl group] methyl }-1H-pyrrolo-[2,3-b] pyridine (43.1g, 0.174mol) De diox (300mL) solution is added drop-wise to the pyridine hydrobromide perbromide (in 277g, 0.868mol) De diox (300mL) solution.Use overhead mechanical stirrer with reactant in stirring at room.After 60 minutes, with reaction mixture water (300mL) termination reaction of two-phase and use ethyl acetate extraction.(2 * 300mL), the organic layer of merging washes (4 * 300mL with water to water layer with the ethyl acetate washing; Final washings pH is 5～6), then use salt solution (300mL) washing, through MgSO ₄Drying is filtered and concentrating under reduced pressure.Crude product is dissolved in immediately methylene dichloride and solution is filtered the silica gel short column, with the methylene dichloride wash-out until garnet is eluted from post fully.Then filtrate use salt water washing (400mL) with saturated sodium bicarbonate aqueous solution washing (400mL), through dried over mgso and vacuum concentration, obtains title compound.MS：m/z＝423(M+1)。

Step is (TMS) oxyethyl group C.1-{[2-] methyl }-1,3-dihydro-2H-pyrrole Cough up also [2,3-b] pyridin-2-ones

With zinc (100g, 1.54mol) be added to 3,3-two bromo-1-{[2-(TMS) oxyethyl groups] methyl }-1,3-dihydro-2 h-pyrrole also [2,3-b] pyridin-2-ones (65g, 0.154mol) is in the solution of THF (880mL) and saturated aqueous ammonium chloride (220mL).After 3 hours, reactant is filtered and vacuum concentration.Resistates is assigned in ethyl acetate and the water, forms white precipitate.With two-layer filtration over celite filter bed, separates two.Water layer washs (2x) with ethyl acetate, and the organic layer of merging washes with water, through dried over mgso, filters also concentrated.Crude product filters the silica gel short column, and use methylene dichloride: ethyl acetate-90: 10 wash-out with the elutriant concentrating under reduced pressure, obtains title compound.MS：m/z＝265(M+1)。

Step D. (±)-2 '-oxo-1 '-{ [2-(TMS) oxyethyl group] methyl }- 1,1 ', 2 ', 3-tetrahydrochysene spiral shell [indenes-2,3 '-pyrrolo-[2,3-b] pyridine]-the 5-methyl-formiate

Toward 1,2-two (brooethyl)-4 benzoic acid methyl esters (9.20g, 28.6mmol) and 1-{[2-(TMS) oxyethyl group] methyl-1,3-dihydro-2 h-pyrrole also [2,3-δ] pyridin-2-ones (7.55g, 28.6mmol) DMF (70mL) solution in add cesium carbonate (9.78g, 30.0mmol).After 4 hours, reaction mixture is assigned to Et ₂O (100mL) and H ₂Among the O (100mL).Water layer is further used Et ₂O extraction (2 * 100mL).The organic layer H that merges ₂The O washing (2 * 100mL), then use salt water washing (100mL), again through dried over mgso, filter and concentrating under reduced pressure.Crude product is used hexane through the silica gel chromatography purifying: EtOAc-85: 15～70: 30 gradient elutions obtain title compound.MS：m/z＝425(M+1)。

Step e. (±)-2 '-oxo-1,1 ', 2 ', 3-tetrahydrochysene spiral shell [indenes-2,3 '-pyrrolo-[2,3-b] Pyridine]-5-formic acid

Toward (±)-2 '-oxo-1 '-{ [2-(TMS) oxyethyl group] methyl }-1,1 ', 2 ', 3-tetrahydrochysene spiral shell [indenes-2,3 '-pyrrolo-[2,3-b)] pyridine]-add CF in methylene dichloride (80mL) solution of 5-methyl-formiate (3.65g, 8.60mmol) ₃CO ₂H (40mL, 52mmol), and with the gained mixture in stirring at room after 18 hours, vacuum concentration.Resistates is dissolved in CH ₂Cl ₂(100mL) and with quadrol (2.3mL, 34.4mmol) process.With reaction mixture stirring at room 18 hours, then with saturated sodium bicarbonate aqueous solution dilution (50mL).Remove organic layer, water layer is further used dichloromethane extraction (2 * 100mL).The organic layer that merges, filters and vacuum concentration then through dried over mgso with salt water washing (50mL).Crude product is used CH through the silica gel chromatography purifying ₂Cl ₂: MeOH-97: 3 wash-outs, obtain 2 '-oxo-1,1 ', 2 ', the brown solid of 3-tetrahydrochysene spiral shell [indenes-2,3 '-pyrrolo-[2,3-5] pyridine]-5-methyl-formiate.This solid is dissolved in MeOH (22mL) and adds 1N sodium hydroxide (25.4mL, 25.4mmol).Reaction mixture 60 ℃ of heating 18 hours, is then made it cooling.This mixture is by adding 6N HCl acidifying, and filtering separation gained precipitation washes with water and vacuum-drying.Obtain the title compound of near-white solid.MS：m/z＝281(M+1)。

Intermediate 11

Spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1H)-ketone dihydrochloride

Steps A .1-{[2-TMS) oxyethyl group] methyl }-the 1H-pyrrolo-2,3-b] Pyridine

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 16.2g, 0.404mol) be added to 7-azaindole (39.8g, 0.337mol) through gradation in 25 minutes and in the solution of DMF (200mL) and with this mixture, stirred 1 hour.Then slowly added 2-(TMS) oxyethyl group methyl chloride (71.8mL, 0.404mol) through 15 minutes, and make the temperature of reaction mixture keep below 10 ℃.After 1 hour, reaction water (500mL) stop and with mixture with dichloromethane extraction (5 * 300mL).The organic layer salt water washing that merges is through MgSO ₄Drying is filtered, and is concentrated and dry under high vacuum, obtains title compound.MS：m/z＝249(M+1)。

Step B.3,3-two bromo-1-{[2-(TMS) oxyethyl groups] methyl-1,3-two Hydrogen-2H-pyrrolo-[2.3-b] pyridin-2-ones

1-{[2-(TMS) oxyethyl group that steps A is obtained] methyl }-1H-pyrrolo-[2,3-b] pyridine (43.1g, 0.174mol) De diox (300mL) solution was added drop-wise to the pyridine hydrobromide perbromide (in the suspension in 277g, the 0.868mol) Zai diox (300mL) through 30 minutes.With overhead mechanical stirrer at the stirring at room reactant.After 60 minutes, with reaction mixture water (300mL) termination reaction of two-phase and use ethyl acetate extraction.(2 * 300mL), the organic layer of merging washes (4 * 300mL with water to water layer with the ethyl acetate washing; Final washings pH is 5～6), then use salt solution (300mL) washing, through MgSO ₄Drying is filtered and concentrating under reduced pressure.Crude product is dissolved in immediately methylene dichloride and solution is filtered the silica gel short column, with the methylene dichloride wash-out until garnet is eluted from post fully.Then filtrate use salt water washing (400mL) with saturated sodium bicarbonate aqueous solution washing (400mL), through dried over mgso and vacuum concentration, obtains title compound.MS：m/z＝423(M+1)。

Step D. spiral shell [ring penta-3-alkene-1,3 '-pyrrole [2,3-b] pyridine-2 ' (1 ' H)-ketone slightly also

Toward suitable-1,4-dichloro-2-butene (1.98g, 15.8mmol) and 1-{[2-(TMS) oxyethyl group] methyl-1,3-dihydro-2 h-pyrrole also [2,3-b] pyridin-2-ones (3.49g, 13.2mmol) add cesium carbonate (10.7g, 32.9mmol) in the solution in DMF (175mL).After 24 hours, reaction mixture is assigned to Et ₂O (200mL) and H ₂Among the O (200mL).Water layer is further used Et ₂O extraction (2 * 200mL).The organic layer that merges wash with water (2 * 100mL), then use salt water washing (100mL), through dried over mgso, filter and concentrating under reduced pressure.In methylene dichloride (150mL) solution of this product, add trifluoroacetic acid (150mL).After 1 hour, reactant is concentrated, be dissolved in EtOH (150mL) and add 2N HCl (150mL).This mixture was 45 ℃ of heating 48 hours.Mixture is concentrated, with the saturated sodium bicarbonate aqueous solution washing, with dichloromethane extraction (2x).The organic layer that merges is dry and concentrated.Crude product is through the silica gel chromatography purifying, and with 0～5% methyl alcohol: the dichloromethane gradient wash-out obtains title compound (0.62g).MS：m/z＝187.1(M+1)。

Step e .3,4-dihydroxyl spiral shell [pentamethylene-1,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H) -ketone

Toward Trimethylamine 99-N-oxide dihydrate (408mg, 3.67mmol) and spiral shell [ring penta-3-alkene-1,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone (622mg, 3.34mmol) adds perosmic anhydride (the 2-methyl-2-propanol solution of 25 μ L 2.5%) in the mixture of methylene dichloride (115mL).After 24 hours, that reaction mixture is concentrated.Crude product is loaded on the silicagel column with minimum methyl alcohol, and with 5～20% methyl alcohol: the dichloromethane gradient wash-out obtains title compound (0.63g).MS：m/z＝221.0(M+1)。

Step F .2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] Pyridine]-the 1-t-butyl formate

Toward 3,4-dihydroxyl spiral shell [pentamethylene-1,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone (640mg, 2.91mmol) was at 3: 1 ethanol: add sodium periodate (622mg, 2.91mmol) in the mixture in the water (160mL).Treat that raw material consumption is complete, ammonium hydroxide (50mL) is added reaction mixture lentamente.Add palladium hydroxide (200mg, 20%) and with reactant in 50psi hydrogenation.After 24 hours, add the 200mg palladium hydroxide and make hydrogenation proceed 24 hours.With reaction mixture filtration over celite and concentrated.Product is dissolved in DMF (10mL), behind the adding tert-Butyl dicarbonate (635mg, 2.91mmol), adds triethylamine (0.811mL, 5.82mmol).After 24 hours, reactant is with saturated aqueous sodium carbonate dilution and with extracted with diethyl ether (3x).The organic layer that merges washes (3x) with water, and is dry and concentrated.Crude product is through the silica gel chromatography purifying, and with 0～10% methyl alcohol: the dichloromethane gradient wash-out obtains title compound (489mg).MS：m/z＝304.1(M+1)。

Step G. spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone dihydrochloride

With 2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-1-t-butyl formate (451mg, 1.49mmol) is dissolved in ethyl acetate (3mL) and at room temperature adds 4N hydrochloric acid De diox (7.5mmol) solution.After 24 hours, vacuum is removed volatile matter and is obtained title compound (404mg).MS?204.1(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ8-31(d，J＝7.1Hz，1H)，8.20(d，J＝6.1Hz，1H)，7.45(dd，J＝6.8，6.8Hz，1H)，3.74(brdd，2H)，3.47(brdd，2H)，2.35(brddd，2H)，2.21(brd，2H)。

Intermediate 12

Spiroperidol-4,4 '-pyridine-[2,3-d] oxazine]-2 ' (1 ' H)-ketone

Steps A .[6-chloropyridine-2-yl] t-butyl carbamate

Toward 2-amino-6-chloropyridine (25.0g, 194.5mmol) and so two um hexamethyl two silazide (1.0M; 427.8mL, add tetrahydrofuran (THF) (175mL) solution of tert-Butyl dicarbonate (46.69g, 213.9mmol) in tetrahydrofuran (THF) 427.8mmol) (175mL) solution.After 48 hours, reaction mixture is concentrated, and resistates is assigned among ethyl acetate (150mL) and the 1NHCl (500mL).Water layer is further used ethyl acetate extraction (2x).The organic layer that merges washs with saturated sodium bicarbonate aqueous solution, through dried over mgso, filters and concentrates.The resistates crude product is dissolved in the 60 ℃ of a small amount of ethanol of trying one's best carries out recrystallization.Make the solution cool to room temperature, add entry.The solid of filtering-depositing is also dry, obtains title compound (33.45g).MS：m/z＝173.0(M- ^tBu)。

Step B.7 '-chloro-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyridine And [2,3-d] [1,3] oxazine]-1-formic acid benzyl ester

With 10 minutes, add n-Butyl Lithium (2.5M in tetrahydrofuran (THF) (180mL) solution of past-20 ℃ N,N,N′,N′ tetramethylethylene diamine (22.3mL, 147.6mmol); 59.0mL, 147.6mmol).After 30 minutes, mixture is cooled to-78 ℃ of tetrahydrofuran (THF) (60mL) solution that also add (6-chloropyridine-2-yl) t-butyl carbamate (15.0g, 65.6mmol) with 15 minutes.2.5 after hour, with tetrahydrofuran (THF) (60mL) solution that added N-carbobenzoxy-(Cbz)-4-piperidone (23.0g, 98.4mmol) in 10 minutes.Make reaction mixture be warming to room temperature.After 1 hour, reactant is heated to 40 ℃.After 18 hours, make the mixture termination reaction with saturated sodium bicarbonate aqueous solution, mixture dichloromethane extraction (3x).The organic extract liquid water, the salt water washing that merge through dried over mgso, are filtered and are concentrated.The resistates crude product is dissolved in 65 ℃ of ethanol (450mL) carries out recrystallization.Solution is placed-20 ℃ refrigerator.After 18 hours, the solid of filtering-depositing, with the ether washing, drying obtains title compound (11.9g).MS：m/z＝388.0(M+1)。

Step C. spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone

With palladium (10% palladium charcoal; 1.5g) be added to 7 '-chloro-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-solution of the ethanol (150mL) of pyrido [2,3-d] [1,3] oxazine]-1-formic acid benzyl ester (3.01g, 7.76mmol) in.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 24 hours, add other palladium (10% palladium charcoal; 0.5g).After 4 hours, with mixture filtration over celite and concentrated, obtain title compound (1.62g).MS?220.1(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ8.26(dd，J＝1.7，5.0Hz，1H)，7.69(dd，J＝1.6，7.7Hz，1H)，7.16(dd，J＝5.0，7.7Hz，1H)，3.49-3.42(m，4H)，2.38-2.25(m，4H)。

Intermediate 13

1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 (1 ' H)-ketone

Steps A .7 '-chloro-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-formic acid benzyl ester

Toward 0 ℃ 7 '-chloro-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-add in DMF (14mL) solution of 1-formic acid benzyl ester (0.56g, 1.43mmol) two (TMS) Lithamide (2.86mL 1M solution, 2.86mmol), then add methyl iodide (0.11mL, 2.28mmol).After 1 hour, add other methyl iodide (0.55mL, 1.14mmol).After 1 hour, reactant dilutes with ethyl acetate again, and water (3x) and salt solution extraction through dried over mgso, are filtered and concentrating under reduced pressure.Crude product is through the silica gel chromatography purifying, and with 0～4% methyl alcohol: the dichloromethane gradient wash-out obtains title compound (0.47g).MS?402.0(M+1)。

Step B.1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)- Ketone

10% palladium charcoal (230mg) is added to 7 '-chloro-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-solution of the MeOH (40mL) of 1-formic acid benzyl ester (0.47g, 1.17mmol) in.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 4 hours, with mixture filtration over celite and concentrated, obtain title compound (0.35g).MS?234(M+1)。

Intermediate 14

1 '-methylspiro [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketoneThe method preparation of describing in the basic preparation according to intermediate 13.

Intermediate 15

3-methyl isophthalic acid-piperidin-4-yl-1,3-dihydro-2H-imidazo [4,5-b] pyridine-2 -ketone

The method preparation of describing in the basic preparation according to intermediate 13.

Intermediate 16

1-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)- Ketone

Steps A .7 '-chloro-1 '-(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-formic acid benzyl ester

Toward 0 ℃ 7 '-chloro-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-add in DMF (4mL) solution of 1-formic acid benzyl ester (0.20g, 0.51mmol) two (TMS) Lithamide (2.86mL 1M solution, 2.86mmol), then add chloromethyl methyl ether (0.094mL, 1.01mmol).0.5 after hour, reactant dilutes with ethyl acetate, water (3x) and salt solution extraction through dried over mgso, are filtered and concentrating under reduced pressure.Crude product is through the silica gel chromatography purifying, and with 0～20% ethyl acetate: the dichloromethane gradient wash-out obtains title compound (0.21g).MS?432.1(M+1)。

Step B.1-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]- 2 ' (1 ' H)-ketone

10% palladium charcoal (103mg) is added to 7 '-chloro-1 '-(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-MeOH (10mL) solution of 1-formic acid benzyl ester (0.21g, 0.48mmol) in.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 4 hours, with mixture filtration over celite and concentrated, obtain title compound (0.14g).MS?264(M+1)。

Intermediate 17

The 1H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone

Steps A .4-[2-methoxyl group-2-oxygen ethylidene] piperidines-1-formic acid benzyl ester

Benzene (100mL) solution of N-carbobenzoxy-(Cbz)-4-piperidone (5.0g, 21.4mol) and (the inferior positive phosphorus base of triphenyl) methyl acetate (10.0g, 30.0mmol) was heated 48 hours at 75 ℃.Reactant is concentrated, and with ether dilution, filtering precipitation, filtrate (rinsate) is concentrated.Crude product is through the silica gel chromatography purifying, and with 20～60% ethyl acetate: hexane obtains title compound (5.25g).MS：m/z＝290.1(M+1)。

Step is (2-methoxyl group-2-oxygen ethyl)-3 B.4-, 6-dihydropyridine-1 (2H)-formic acid Benzyl ester

DMF (120mL) solution at stirring at room 4-(2-methoxyl group-2-oxygen ethylidene) piperidines-1-formic acid benzyl ester (5.25g, 18.1mol) and 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene (2.71mL, 18.1mol).After 3 days, the reactant dilute with water is also used extracted with diethyl ether (4x).Merge organic phase, through dried over mgso, filter and concentrating under reduced pressure.Crude product is through the silica gel chromatography purifying, and with 5～30% ethyl acetate: the hexane gradient wash-out obtains title compound (2.44g).MS：m/z＝290.1(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ7.30-7.25(m，5H)，5.5(brs，1H)，5.2(s，2H)，4.0(brs，2H)，3.7(s，3H)，3.6(brs，2H)，3.0(s，2H)，2.2(brs，2H)。

Step is bromopyridine-2-yl C.4-{2-[(3-) amino]-2-oxygen ethyl }-3, the 6-dihydro Pyridine-1 (2H)-formic acid benzyl ester

With trimethyl aluminium (2.0M, 2.05mL, 4.10mol) slowly be added to 0 ℃ 4-(2-methoxyl group-2-oxygen ethyl)-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester (0.79g, 2.73mol) and 2-amino-3-bromopyridine (0.520g, 3.00mmol) 1, in 2-ethylene dichloride (15mL) solution.After 30 minutes, reactant is heated to 55 ℃ kept 48 hours.Reaction is by careful adding saturated sodium bicarbonate aqueous solution termination and with mixture dichloromethane extraction (4x).The organic layer that merges, filters and concentrates through dried over mgso with 1N Seignette salt, salt water washing.Crude product is through the silica gel chromatography purifying, and with 50～100% ethyl acetate: the hexane gradient wash-out obtains title compound (2.44g).MS：m/z＝430.0(M+1)。

Step is ((3-bromopyridine-2-yl) { [2-(TMS) oxyethyl group] first D.4-[2- Base } amino)-2-oxygen ethyl]-3,6-dihydropyridine-1 (2H) formic acid benzyl ester

Under 0 ℃, through 10 minutes, with sodium hydride (60% mineral oil dispersion; 117mg, 4.88mol) gradation adding 4-{2-[(3-bromopyridine-2-yl) amino]-2-oxygen ethyl }-3, in THF (15mL) solution of 6-dihydropyridine-1 (2H)-formic acid benzyl ester (1.91g, 4.43mol).0.5 after hour, slowly add 2-(TMS) oxyethyl group methyl chloride (0.861mL, 4.88mol), make simultaneously temperature of reaction keep below 10 ℃.After 4 hours, add sodium hydride (60mg) and 2-(TMS) oxyethyl group methyl chloride (0.45ml) and make reactant be warming to ambient temperature overnight.Use the saturated aqueous ammonium chloride termination reaction, mixture dichloromethane extraction (3x).The organic layer that merges filters and concentrates through dried over mgso.Crude product is through the silica gel chromatography purifying, and with 40～70% ethyl acetate: the hexane gradient wash-out obtains title compound (1.51g).MS：m/z＝560.2(M+1)。

Step e .2-oxo-1-{[2-(TMS) oxyethyl group] methyl }-2,2 ', 3,3 '- Tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-the formic acid benzyl ester

Toward N-methylcyclohexylamine (0.042mg, 0.20mmol) and 4-[2-((3-bromopyridine-2-yl) { [2-(TMS) oxyethyl group] methyl } amino)-2-oxygen ethyl]-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester (100mg, 0.178mmol add two (tri-butyl phosphine) palladium (0) (9mg, 0.018mmol) in) De diox (2mL) mixture.After 5 minutes, reactant is heated to 50 ℃.After 90 minutes, add two (tri-butyl phosphine) palladium (0) (9mg, 0.018mmol).In 50 ℃ after 30 minutes, with the reaction mixture dilute with water and with extracted with diethyl ether (3x).The organic layer that merges filters and concentrates through dried over mgso.Crude product is through the silica gel chromatography purifying, and with 5～60% ethyl acetate: the hexane gradient wash-out obtains title compound (68mg).MS：m/z＝480.2(M+1)。

Step F .1H-spiral shell [1,8-naphthyridines-4.4 '-piperidines]-2 (3H)-ketone

Toward 2-oxo-1-{[2-(TMS) oxyethyl group] methyl }-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-add trifluoroacetic acid (10mL) in the mixture of formic acid benzyl ester (384mg, 0.800mmol) in methylene dichloride (10mL).After 3 hours, reactant is concentrated, with methylene dichloride (10mL) dilution and adding quadrol (720mg, 12.0mmol).After 18 hours, reactant is concentrated, and resistates is assigned in saturated sodium bicarbonate aqueous solution and the methylene dichloride, separates two.Water is with other dichloromethane extraction (2x).Merge organic layer, dry and concentrated.10% palladium charcoal (300mg) is added in ethanol (10mL) solution of resistates.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 24 hours, with mixture filtration over celite and concentrated, obtain title compound (130mg).MS?218.1(M+1)。 ¹H?NMR(500MHz，CD ₃OD)δ8.14(dd，J＝1.6，5.0Hz，1H)，7.80(dd，J＝1.6，7.7Hz，1H)，7.10(dd，J＝5.0，7.7Hz，1H)，2.98-2.95(m，4H)，2.78(s，2H)，1.96-1.90(m，2H)，1.69(brd，J＝11.5Hz，2H)。

Intermediate 18

4-piperidin-4-yl pyridazine-3 (2H)-ketone

Steps A: 4-[1-(ethoxy carbonyl) fourth-3-alkene-1-yl] piperidines-1-formic acid benzyl Ester

Past-78 ℃ 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester (5.02g, 16.4mmol) tetrahydrofuran (THF) (90mL) solution in add hexamethyl dimethyl silanyl Lithamide (1.0M THF liquid, 18.1mL, 18.1mmol).After 1 hour, add allyl bromide 98 (2.19g, 18.1mmol), reactant was stirred 0.5 hour under this temperature, then be warming to 25 ℃.After 3 hours, also use ethyl acetate extraction (2x) with the saturated aqueous ammonium chloride termination reaction.The organic layer extraction liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% hexane → 40% hexane/ethyl acetate), obtain title compound (4.08g).MS?346.1(M+1)。

Step B: benzyl 4-[1-(ethoxy carbonyl)-3-oxygen propyl group] piperidines-1-manthanoate

With 4-[1-(ethoxy carbonyl) fourth-3-alkene-1-yl] piperidines-1-formic acid benzyl ester (4.08g, 11.8mmol) be dissolved in the tetrahydrofuran (THF) (45mL), and adding perosmic anhydride (0.45mL, 2.5% butanol solution), then water (37mL) solution that adds sodium periodate (7.57g, 35.4mmol).After 24 hours, with reactant with the dilution of the saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, and with ethyl acetate extraction (4x).The organic extract liquid that merges filters and concentrates through dried over sodium sulfate.Through silica gel chromatography purifying (50% hexane/ethyl acetate → 100% ethyl acetate), obtain title compound (2.39g).MS?348.1(M+1)。

Step C:4-(3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester

With 4-[1-(ethoxy carbonyl)-3-oxygen propyl group] piperidines-1-formic acid benzyl ester (2.39g, 6.89mmol) is dissolved in acetic acid (100mL) and adds hydrazine (4.42g, 137mmol).This mixture after 24 hours, is concentrated into dried 50 ℃ of heating.Resistates is with saturated sodium bicarbonate aqueous solution dilution and with dichloromethane extraction (3x), and the organic layer of merging is dry, and concentrates, and obtains white solid (1.90g).This material is dissolved in acetonitrile (20mL), adds cupric chloride (II) (1.62g, 12.0mmol) and reactant is heated to 50 ℃.After 2 hours, reactant methylene dichloride filtration over celite.Filtered solution washes (75mL) with water, and water is washed (3x) with the methylene dichloride backwash.The organic washings that merges is with 1N HCl washing, and is dry and concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 88% methylene chloride/methanol), obtain title compound (0.90g).MS?314.1(M+1)。

Step D:4-piperidin-4-yl pyridazine-3 (2H)-ketone

With the hydrogenation 4 hours in the presence of hydrogen balloon of 4-(3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester (0.90mg, 2.88mmol) and the solution of 10%Pd/C (500mg) in ethanol (25mL).With the reactant filtration over celite, with washing with alcohol and concentrated, obtain title compound (465mg).MS?180.1(M+1)。

Intermediate 19

6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone

Steps A: 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester

Chloro (chlorido) carbonic acid benzyl ester (10.5g, 61.3mmol) is added in methylene dichloride (320mL) solution of piperidin-4-yl ethyl acetate (10.0g, 58.4mmol) and yellow soda ash (46.2g, 438mmol).After 18 hours, reaction mixture is filtered and concentrates.Through silica gel chromatography purifying [75% hexane/ethyl acetate → 50% hexane/ethyl acetate)], obtain title compound (17.6g).MS?306.1(M+1)。

Step B:4-[1-(ethoxy carbonyl)-3-methyl fourth-3-alkene-1-yl] piperidines-1 -formic acid benzyl ester

Under-78 ℃, with hexamethyl disilazanylamino lithium (1.0M in THF; 18.0mL, 18.0mmol) be added in tetrahydrofuran (THF) (90mL) solution of 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester (5.0g, 16.4mmol).After 40 minutes, add 3-bromo-2-methyl-prop-1-alkene (1.81mL, 18.0mmol) and make reaction mixture be warming to room temperature.After 16 hours, add the saturated aqueous ammonium chloride termination reaction and use ethyl acetate extraction (2x).The organic layer that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% hexane → 40% hexane/ethyl acetate), obtain title compound (2.88g).MS?360.2(M+1)。

Step C:4-[1-(ethoxy carbonyl V3-hydrogen butyl] piperidines-1-formic acid benzyl ester

With perosmic anhydride (2.5wt.% t-butanol solution; 0.3mL, 0.001mmol) be added to 4-[1-(ethoxy carbonyl)-3-methyl fourth-3-alkene-1-yl] and in tetrahydrofuran (THF) (30mL) solution of piperidines-1-formic acid benzyl ester (2.88g, 8.01mmol).Water (26mL) solution of sodium periodate (5.14g, 24.0mmol) is added to reaction mixture.After 5 days, reactant is with the dilution of the saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution and with ethyl acetate extraction (3x).The organic washings that merges is dry through S-WAT, filters and the concentrated title compound that obtains.MS362.2(M+1)。

Step D:4-(6-methyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1 -formic acid benzyl ester

Hydrazine (4.72mL, 148.7mmol) is added to 4-[1-(ethoxy carbonyl)-3-oxygen-butyl] in acetic acid (110mL) solution of piperidines-1-formic acid benzyl ester (2.69g, 7.44mmol).Reaction mixture is in 50 ℃ of heating.After 1 hour, that reaction mixture is concentrated.Resistates dilutes with methylene dichloride, neutralizes through saturated sodium bicarbonate aqueous solution.Mixture is with dichloromethane extraction (3x), and the organic extract liquid that merges is also concentrated through dried over mgso, obtains title compound.MS330.2(M+1)。

Step e: 4-(6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1- The formic acid benzyl ester

Cupric chloride (II) is (anhydrous; 2.02g, 15.05mmol) be added in acetonitrile (26mL) solution of 4-(6-methyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester (2.48g, 7.53mmol).Reaction mixture is in 90 ℃ of heating.After 18 hours, this mixture is cooled to room temperature and concentrated. resistates methylene chloride and 1N HCl.Mixture is with dichloromethane extraction (3x), and the organic extract liquid that merges is also concentrated through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (1.45g).MS?328.2(M+1)。

Step F: 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone

With palladium (10% palladium charcoal; 0.70g) be added in ethanol (100mL) solution of 4-(6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester (1.45g, 4.43mmol).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 24 hours, this mixture filtration over celite is also concentrated, obtains title compound (0.86g).MS?194.1(M+1)。

Intermediate 20

6-phenyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone

Steps A: [1-(brooethyl) vinyl benzene

N-bromine succinimide (52.0g, 292mmol) and benzoyl peroxide (2.0g, 8.0mmol) are added in tetracol phenixin (200mL) solution of isopropenylbenzene (82.0g, 694mmol).Reaction mixture is heated to backflow.After 18 hours, add other N-bromine succinimide (30.0g, 168mmol).After 18 hours, make the solid in this mixture cool to room temperature and this mixture of filtering.With filtrate concentrated and through the vacuum distilling purifying (95-120 ℃, 10torr).Isolated mixture obtains title compound through silica gel chromatography purifying (100% hexane).

Step B:4-[1-(methoxycarbonyl)-3-phenyl fourth-3-alkene-1-yl] piperidines-1 -formic acid benzyl ester

Under-78 ℃, with hexamethyl disilazanylamino lithium (1.0M THF solution; 7.31mL, 7.31mmol) be added in tetrahydrofuran (THF) (35mL) solution of 4-(2-methoxyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester (1.94g, 6.65mmol).After 40 minutes, add [1-(brooethyl) vinyl] benzene (1.08mL, 7.31mmol) and reaction mixture is warming to room temperature.After 18 hours, this mixture is with the saturated aqueous ammonium chloride termination reaction and use ethyl acetate extraction (2x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% hexane → 40% hexane/ethyl acetate), obtain title compound (2.11g).MS?408.2(M+1)。

Step C:4-[1-(methoxycarbonyl)-3-oxo-3-phenyl propyl] piperidines-1-first The acid benzyl ester

With perosmic anhydride (2.5wt% trimethyl carbinol liquid; 0.2mL, 0.001mmol) be added to 4-[1-(methoxycarbonyl)-3-phenyl fourth-3-alkene-1-yl] and in tetrahydrofuran (THF) (20mL) solution of piperidines-1-formic acid benzyl ester (2.11g, 5.19mmol).Water (17mL) solution of sodium periodate (3.33g, 15.6mmol) is added in the reaction mixture.After 18 hours, add the saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction (4x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound.MS410.1(M+1)。

Step D:4-(3-oxo-6-phenyl-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1 -formic acid benzyl ester

Hydrazine (3.31mL, 104mmol) is added to 4-[1-(methoxycarbonyl)-3-oxo-3-phenyl propyl] in acetic acid (70mL) solution of piperidines-1-formic acid benzyl ester (2.14g, 5.22mmol).With reaction mixture in 50 ℃ of heating.After 1 hour, that reaction mixture is concentrated.Resistates dilutes with methylene dichloride, neutralizes through saturated sodium bicarbonate aqueous solution.Mixture dichloromethane extraction (3x), and the organic extract liquid that merges is also concentrated through dried over mgso, obtain title compound.MS?392.1(M+1)。

Step e: 4-(3-oxo-6-phenyl-2,3-dihydrogen dazin-4-yl) piperidines-1- The formic acid benzyl ester

Cupric chloride (II) is (anhydrous; 1.27g, 9.45mmol) be added in acetonitrile (16mL) solution of 4-(3-oxo-6-phenyl-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester (1.85g, 4.73mmol).Reaction mixture is heated to 90 ℃.After 2 hours, this mixture makes cool to room temperature and concentrated.Methylene dichloride is added in this enriched mixture, then adds hydrochloric acid (the 1N aqueous solution).Mixture also concentrates through dried over mgso with dichloromethane extraction (3x) and with the organic extract liquid that merges.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (1.1g).MS?390.1(M+1)。

Step F: 6-phenyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone

With palladium (10% palladium charcoal; 0.50g) be added in ethanol (50mL) solution of 4-(3-oxo-6-phenyl-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester (1.10g, 2.82mmol).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 24 hours, this mixture filtration over celite is also concentrated, obtains title compound (709mg).MS?256.2(M+1)。

Intermediate 21 and intermediate 22

6-cyclopropyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone and 4-piperidin-4-yl-6 -propyl group pyridazine-3 (2H)-ketone

Steps A: 4-[3-bromo-1-(ethoxy carbonyl] fourth-3-alkene-1-yl] piperidines-1- The formic acid benzyl ester

Under-78 ℃, with hexamethyl disilazanylamino lithium (1.0M in THF; 7.20mL, 7.20mmol) be added in tetrahydrofuran (THF) (30mL) solution of 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester (2.0g, 6.55mmol).After 40 minutes, add 2,3-dibromo third-1-alkene (0.70mL, 7.20mmol).After 2 hours, reaction mixture is warming to room temperature.After 18 hours, this mixture is with the saturated ammonium chloride termination reaction and use ethyl acetate extraction (2x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (80% hexane/ethyl acetate → 40% hexane/ethyl acetate), obtain title compound (603mg).MS424.0(M)。

Step B:4-[3-cyclopropyl-1-(ethoxy carbonyl) fourth-3-alkene-1-yl] piperidines- 1-formic acid benzyl ester

With dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture (137mg, 0.187mmol) be added to 4-[3-bromo-1-(ethoxy carbonyl) fourth-3-alkene-1-yl] in ether (6mL) solution of piperidines-1-formic acid benzyl ester (795mg, 1.87mmol).Reaction mixture is cooled to 0 ℃ and cyclopropyl bromination magnesium (0.544g, 3.75mmol) adding.After 1 hour, this mixture is warming to room temperature.After 1 hour, this mixture is risen again to 0 ℃, and gradation adds other dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture (137mg, 0.187mmol) and cyclopropyl bromination magnesium (544mg, 3.75mmol).This mixture is warming to room temperature.After 18 hours, add hydrochloric acid (10% aqueous solution) and with mixture with extracted with diethyl ether (2x).The organic extract liquid that merges, filters and concentrates through dried over mgso with saturated sodium bicarbonate aqueous solution, water washing.Through silica gel chromatography purifying (100% hexane → 50% hexane/ethyl acetate), obtain title compound (173mg).MS?386.2(M+1)。

Step C:4-[3-cyclopropyl-1-(ethoxy carbonyl)-3-oxygen propyl group] piperidines-1-first The acid benzyl ester

Perosmic anhydride (2.5wt% butanol solution; 17 μ L, 0.001mmol) be added to 4-[3-cyclopropyl-1-(ethoxy carbonyl) fourth-3-alkene-1-yl] in tetrahydrofuran (THF) (2mL) solution of piperidines-1-formic acid benzyl ester (173mg, 0.45mmol).Water (1.5mL) solution of sodium periodate (290mg, 1.35mmol) is added to reaction mixture.After 18 hours, add the saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction (4x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound.MS388.1(M+1)。

Step D:4-(6-cyclopropyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines -1-formic acid benzyl ester

Hydrazine (0.3mL, 9.6mmol) is added to 4-[3-cyclopropyl-1-(ethoxy carbonyl)-3-oxygen propyl group] in acetic acid (7mL) solution of piperidines-1-formic acid benzyl ester (186mg, 0.48mmol).With reaction mixture in 50 ℃ of heating.After 1 hour, reaction mixture is concentrated.Resistates neutralizes with the methylene dichloride dilution and with saturated sodium bicarbonate aqueous solution.Mixture dichloromethane extraction (3x), and will be also concentrated through dried over mgso with the organic extract liquid that merges, title compound obtained.MS?356.2(M+1)。

Step e: 4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1 -formic acid benzyl ester

(II) is (anhydrous for cupric chloride; 101mg, 0.75mmol) be added in acetonitrile (16mL) solution of 4-(6-cyclopropyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester (134mg, 0.38mmol).Reaction mixture is heated to 90 ℃.After 18 hours, this mixture is cooled to room temperature and concentrated.Methylene dichloride is added in this enriched mixture, then adds hydrochloric acid (the 1N aqueous solution).Mixture also concentrates through dried over mgso with dichloromethane extraction (3x) and with the organic extract liquid that merges.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (54mg).MS?354.1(M+1)。

Step F: 6-cyclopropyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone and 4-piperidines-4 -Ji-6-propyl group pyridazine-3 (2H)-ketone

With palladium (10% palladium charcoal; 50mg) be added in ethanol (20mL) solution of 4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester (54mg, 0.15mmol).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 1 hour, this mixture filtration over celite is also concentrated, obtains the mixture (33mg) of two kinds of title compounds of 1: 1.MS 220.2 (M+1) and MS 222.2 (M+1).

Intermediate 23

The 1-methyl isophthalic acid, 3,8-thriazaspiro [4.5] decane-2,4-diones

Steps A: benzyl 4-cyano group-4-(methylamino) piperidines-1-manthanoate

Under 0 ℃, water (5mL) solution of potassium cyanide (2.79g, 42.9mmol) is added to 4-oxo-piperidine-1-formic acid benzyl ester (10.0g, 42.9mmol) and methylamine hydrochloride (2.90g, 42.9mmol) water/methyl alcohol (1: 1; In solution 10mL).Reaction mixture is warming to room temperature.After 48 hours, add other methylamine hydrochloride (1.45g, 21.4mmol).After 18 hours, this mixture dilutes with ether, and with ethyl acetate extraction (3x).The organic extract liquid that merges is through dried over mgso and be concentrated into the 50mL volume.In this solution, passed into HCl gas 5 minutes.The solid filtering that is settled out in the solution is also used ether (3x), ethyl acetate (3x) washing, and drying under reduced pressure obtains the hydrochloride of title compound.MS?274.1(M+1)。

Step B:1-methyl-2,4-dioxo-1,3,8-thriazaspiro [4.5] decane-8-formic acid Benzyl ester

Water (9mL) solution of potassium cyanide (5.74g, 70.8mmol) is added drop-wise in acetic acid (27mL) solution of hydrochloride of 4-cyano group-4-(methylamino) piperidines-1-formic acid benzyl ester (9.68g, 35.4mmol).This reaction mixture is in 50 ℃ of heating.After 1 hour, in this mixture impouring cold water (200mL).This mixture ethyl acetate extraction (4x), and the organic extract liquid that merges is also concentrated through dried over mgso.Add HCl solution (10% aqueous solution; 40mL) and with this mixture in 50 ℃ of heating.After 15 minutes, reaction mixture is cooled to room temperature.Solid filtering with precipitation washes with water, and drying under reduced pressure, obtains title compound.MS?318.1(M+1)。

Step C:1-methyl isophthalic acid, 3,8-thriazaspiro [4.5] decane-2,4-diones

With palladium (10% palladium charcoal; 1.0g) being added to 1-methyl-2,4-dioxo-1,3 is in ethanol (100mL) solution of 8-thriazaspiro [4.5] decane-8-formic acid benzyl ester (7.82g, 24.6mmol).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 2 hours, methyl alcohol (50mL) is added in the reaction mixture also with (1 normal atmosphere) continuation stirring under nitrogen atmosphere of this mixture.After 4 days, this mixture filtration over celite is also concentrated with washing with acetone.This mixture is with acetic acid dilution (50mL).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 2 hours, this mixture filtration over celite, and the concentrated acetate (2.98g) that obtains title compound.MS?184.1(M+1)。

Intermediate 24

3-methyl isophthalic acid H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone

Steps A: 4-(2-methoxyl group-2-oxygen ethylidene) piperidines-1-formic acid benzyl ester

Under 0 ℃, (the inferior phosphoranyl of triphenyl) methyl acetate (10.0g, 30.0mmol) is added in benzene (100mL) solution of 4-oxo-piperidine-1-formic acid benzyl ester (5.0g, 21.4mmol).After 1 hour, reaction mixture is heated to 75 ℃.After 48 hours, the concentrated and adding ether with this mixture.Concentrate with the solid filtering of precipitation and with filtrate.Through silica gel chromatography purifying [80% hexane/ethyl acetate → 40% hexane/ethyl acetate)], obtain title compound (5.25g).MS290.1(M+1)。

Step B:4-(2-methoxyl group-2-oxygen ethyl)-3,6-dihydropyridine-1 (2H)-formic acid Benzyl ester

With 2,3,4,6,7,8,9,10-decahydro pyrimidine [1,2-α] azepine

(2.71mL, 18.2mmol) is added in DMF (120mL) solution of 4-(2-methoxyl group-2-oxygen ethylidene) piperidines-1-formic acid benzyl ester (5.25g, 18.2mmol).After 3 days, the reaction mixture dilute with water is also used extracted with diethyl ether (4x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying [100% methylene dichloride → 85% dichloromethane/ethyl acetate)], obtain title compound (2.43g).MS?290.1(M+1)。

Step C:4-{2-[(3-bromopyridine-2-yl) amino]-2-oxygen ethyl }-3, the 6-dihydro Pyridine-1 (2H)-formic acid benzyl ester

Under 0 ℃, with trimethyl aluminium (0.91g, 12.61mmol) be added to 4-(2-methoxyl group-2-oxygen ethyl)-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester (2.43g, 8.41mmol) and ethylene dichloride (45mL) solution of 3-bromopyridine-2-amine (1.60g, 9.25mmol) in.Reaction mixture slowly is warming to 55 ℃.After 18 hours, reaction mixture is with the saturated sodium bicarbonate aqueous solution termination reaction and use dichloromethane extraction (4x).The organic extract liquid that merges washs with Rochelle ' s salt (the 1N aqueous solution), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (50% hexane/ethyl acetate → 100% ethyl acetate), obtain title compound (1.91g).MS?430.0(M)。

Step D:4-[2-((3-bromopyridine-2-yl) { [2-(TMS) oxyethyl group] first Base) amino)-and 2-oxygen ethyl]-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester

Under 0 ℃, with sodium hydride (60% oil dispersion; 0.20g, 5.0mmol) slowly be added to 4-{2-[(3-bromopyridine-2-yl) and amino]-2-oxygen ethyl }-3, in tetrahydrofuran (THF) (15mL) solution of 6-dihydropyridine-1 (2H)-formic acid benzyl ester (1.91g, 4.43mmol).After 30 minutes, add [2-(chlorine methoxyl group) ethyl] (trimethylammonium) silane (0.86mL, 4.88mmol).After 4 hours, add other sodium hydride (60% oil dispersion; 0.10g, 2.5mmol), then be [2-(chlorine methoxyl group) ethyl] (trimethylammonium) silane (0.43mL, 2.44mmol).After 18 hours, reaction mixture saturated ammonium chloride termination reaction.The mixture dichloromethane extraction.The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (60% hexane/ethyl acetate → 30% hexane/ethyl acetate), obtain title compound (1.51g).MS560.1(M)。

Step e: 2-oxo-1-{[2-(TMS) oxyethyl group] methyl }-2,2 ', 3,3 '- Tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-the formic acid benzyl ester

With two (three-tertiary butyl phosphine) palladium (0) (9.0mg, 0.018mmol) be added to 4-[2-((3-bromopyridine-2-yl) { [2-(TMS) oxyethyl group] methyl } amino)-2-oxygen ethyl]-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester (0.10g, 0.18mmol) and dicyclohexyl methylamine (in the solution of 42 μ L, 0.196mmol) Zai dioxs (2mL).After 5 minutes, reaction mixture is heated to 50 ℃.1.5 after hour, add two other (three-tertiary butyl phosphine) palladiums (0) (9.0mg, 0.018mmol).After 20 minutes, add entry and with mixture with extracted with diethyl ether (2x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (95% hexane/ethyl acetate → 40% hexane/ethyl acetate), obtain title compound (68mg).MS480.2(M+1)。

Step F: 3-methyl-2-oxo-1-{[2-(TMS) oxyethyl group] methyl }- 2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-the formic acid benzyl Ester

Under-78 ℃, with hexamethyl disilazanylamino lithium (1.0M THF solution; 0.135mL, 0.135mmol) be added to 2-oxo-1-{[2-(TMS) oxyethyl group] methyl-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-tetrahydrofuran (THF) (1mL) solution of formic acid benzyl ester (50.0mg, 0.104mmol) in.After 40 minutes, add methyl iodide (8.0 μ L, 0.135mmol) and reaction mixture slowly is warming to room temperature.After 1 hour, this mixture is with the saturated aqueous ammonium chloride termination reaction and use ethyl acetate extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound.MS494.3(M+1)。

Step G:3-methyl-2-oxo-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines -4,4 '-pyridine]-1 '-the formic acid benzyl ester

With trifluoroacetic acid (4mL, 53.8mmol) be added to 3-methyl-2-oxo-1-{[2-(TMS) oxyethyl group] methyl-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-methylene dichloride (2mL) solution of formic acid benzyl ester (0.10g, 0.20mmol) in.After 2 hours, that reaction mixture is concentrated.Mixture that should be concentrated is with methylene dichloride dilution (2mL) and add ethane-1,2-diamines (4mL).After 1 hour, the concentrated and adding saturated sodium bicarbonate aqueous solution of reaction mixture.Mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso.MS?364.1(M+1)。

Step H:3-methyl isophthalic acid H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone

With 3-methyl-2-oxo-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-formic acid benzyl ester (73mg, 0.20mmol) is with ethanol (10mL) dilution and add palladium (10% palladium charcoal; 100mg).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 6 hours, this mixture diatomite filtration is with ethanol and methanol wash.Filtrate is concentrated, obtain title compound.MS?232.1(M+1)。

Intermediate 25

3-piperidin-4-yl pyridine-2 (1H) ketone

Steps A: the 4-{[(trifluoromethyl) alkylsulfonyl] oxygen }-3,6-dihydropyridine-1 (2H)-formic acid Benzyl ester

Under-78 ℃, with n-Butyl Lithium (2.5M THF solution; 10.8mL, 27.0mmol) be added in tetrahydrofuran (THF) (37mL) solution of diisopropylamine (3.79mL, 27.0mmol).After 5 minutes, reaction mixture is warming to 0 ℃, keeps after 20 minutes, and cooling is risen again to-78 ℃.Under-78 ℃, this mixture is added in tetrahydrofuran (THF) (50mL) solution of 4-oxo-piperidine-1-formic acid benzyl ester (5.26g, 22.5mmol).After 1 hour, add tetrahydrofuran (THF) (12mL) solution of N-phenyl-two (fluoroform sulfimide) (8.85g, 24.8mmol).This mixture is warming to 0 ℃.After 3 hours, this mixture is also concentrated with the saturated sodium bicarbonate aqueous solution termination reaction.Resistates is with the saturated sodium bicarbonate aqueous solution dilution and use extracted with diethyl ether.The organic extract liquid that merges is through dried over mgso and concentrated.Through silica gel chromatography purifying (100% hexane → 60% hexane/ethyl acetate).Through silica gel chromatography purifying (100% methylene dichloride → 93% dichloromethane/ethyl acetate), obtain title compound (3.52g) again.MS?366.0(M+1)。

Step B:2-methoxyl group-3 ', 6 '-dihydro-3,4 '-dipyridyl (bipyridine)-1 ' (2 ' H) -formic acid benzyl ester

Yellow soda ash (2.0M in water; 4.0mL; 8.09mmol) be added to the 4-{[(trifluoromethyl) alkylsulfonyl] oxygen-3; 6-dihydropyridine-1 (2H)-formic acid benzyl ester (1.26g; 3.45mmol) and (2-methoxypyridine-3-yl) boric acid (0.58g; 3.79mmol) in the solution of DMF (12mL).Add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture (0.25g, 0.345mmol) and with this mixture heating up to 70 ℃.After 2 hours, this mixture is cooled to room temperature and adds entry.This mixture also concentrates through dried over mgso with ethyl acetate extraction and with the organic extract liquid that merges.Through silica gel chromatography purifying (100% hexane → 50% hexane/ethyl acetate), obtain title compound (0.815g).MS?325.2(M+1)。

Step C:4-(2-methoxypyridine-3-yl) piperidines-1-t-butyl formate

With tert-Butyl dicarbonate (0.31g, 1.43mmol) be added to 2-methoxyl group-3 ', 6 '-dihydro-3,4 '-dipyridyl-1 ' (in the ethyl acetate of 2 ' H)-formic acid benzyl ester (0.42g, 1.3mmol) (4mL) solution.Add palladium (10% palladium charcoal; Degassed and recharge nitrogen (3x) 200mg) and with reaction vessel, then recharge hydrogen (1 normal atmosphere).After 3 hours, this mixture filtration over celite is also concentrated, obtains title compound (416mg).MS?293.2(M+1)。

Step D:3-piperidin-4-yl pyridine-2 (1H)-ketone

4-(2-methoxypyridine-3-yl) piperidines-1-t-butyl formate (204mg, 0.70mmol) is added to hydrochloric acid (the 6.0M aqueous solution; 5.81mL, 34.89mmol) in.After 18 hours, the concentrated and drying under reduced pressure of reaction mixture obtains title compound.MS?179.1(M+1)。

Intermediate 26

3,9-diaza spiro [5.5] hendecane-2, the 4-diketone

Steps A: 2,2 '-(1-benzyl piepridine-4,4-two bases) oxalic acid

Sodium hydroxide (173mg, 4.30mmol) is added to 2,2 '-(1-benzyl piepridine-4,4-two bases) oxalic acid diethyl ester (J Med.Chem.2004,47,1900-1918) in the methyl alcohol of (0.50g, 1.44mmol) (5mL) solution.After 1 hour, reaction mixture is warming to 50 ℃.After 18 hours, add other sodium hydroxide (57mg, 1.44mmol).After 2 hours, add hydrochloric acid (the 6.0M aqueous solution; 1.02mL, 6.10mmol) and with this mixture concentrate, obtain the sodium chloride salt of title mixture.MS?292.1(M+1)。

Step B:9-benzyl-3,9-diaza spiro [5.5] hendecane-2,4-diketone

Urea (242mg, 4.03mmol) is added to 2,2 '-(1-benzyl piepridine-4,4-two bases) oxalic acid (390mg, 1.34mmol).This mixture heating up to 160 ℃.After 3 hours, add other urea (242mg, 4.03mmol) and with this mixture heating up to 185 ℃.After 18 hours, add other urea (242mg, 4.03mmol).After 48 hours, reaction mixture makes cool to room temperature and adds ethanol.After 1 hour, with this mixture filtration and with the solid washing with alcohol.Saturated sodium bicarbonate aqueous solution is added in this solid, stirs this suspension until air release is complete.This mixture is filtered and solid is washed with water, and concentrated, obtain title compound (380mg).MS?273.1(M+1)。

Step C:3,9-diaza spiro [5.5] hendecane-2,4-diketone

(20% charcoal drapes over one's shoulders and carries with palladium hydroxide; 100mg) and acetic acid (250 μ L) be added to 9-benzyl-3,9-diaza spiro [5.5] hendecane-2 is in the ethanol of 4-diketone (0.38g, 1.40mmol) (5mL) solution.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 18 hours, this mixture is filtered and concentrates, obtain the acetate (220mg) of title compound.MS?183.1(M+1)。

Intermediate 27

1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-4-ketone

Steps A: 4-(aminocarboxyl)-4-{[(benzyloxy) carbonyl] amino } piperidines-1-formic acid uncle Butyl ester

Toward the 4-{[(benzyloxy) carbonyl] amino }-1-(tertbutyloxycarbonyl) piperidines-4-formic acid (2.09g, 5.52mmol) N, add N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (1.27g in dinethylformamide (10mL) solution, 6.63mmol), I-hydroxybenzotriazole hydrate (0.37g, 2.76mmol) and triethylamine (0.92mL, 6.63mmol), then add ammonia (0.5M dioxane solution; 13.3mL, 6.63mmol).After 18 hours, add saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction.The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 94% methylene chloride/methanol), obtain title compound (0.43g).MS?378.2(M+1)。

Step B:4-{[(benzyloxy) carbonyl] amino }-1-(tertbutyloxycarbonyl) piperidines-4-formic acid

With palladium (10% palladium charcoal; 210mg) be added to 4-(aminocarboxyl)-4-{[(benzyloxy) carbonyl] amino } in ethanol (20mL) solution of piperidines-1-t-butyl formate (0.43g, 1.14mmol).Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 18 hours, this mixture filters and is concentrated, obtains title compound (290mg).

Step C:4-oxo-1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-8-t-butyl formate

Trimethoxy-methane (230mg, 2.16mmol) is added to the 4-{[(benzyloxy) carbonyl] amino-toluene (8mL) solution of 1-(tertbutyloxycarbonyl) piperidines-4-formic acid (0.175g, 0.72mmol) in.Reaction mixture is heated to 90 ℃.After 18 hours, that this mixture is concentrated.Through silica gel chromatography purifying (99% methylene chloride/methanol → 90% methylene chloride/methanol), obtain title compound (76mg).MS?254.1(M+1)。

Step D:1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-4-ketone

With hydrochloric acid (4.0N dioxane solution; 4mL, 16.0mmol) be added to 4-oxo-1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-8-t-butyl formate is (in 60mg, 0.24mmol) De diox (6mL) solution.After 18 hours, the concentrated hydrochloride that obtains title compound of reaction mixture.MS?154.1(M+1)。

Intermediate 28

(3R, 6S)-6-(2,3-the difluorophenyl)-2-sulphur oxa-azepan-amino first of 3-base Tert-butyl acrylate

Steps A: 2-bromo-N-(2,4-dimethoxy-benzyl) third-2-alkene-1-amine

Triethylamine (16.0mL, 114mmol) is added to 2,4-dimethoxy-benzyl amine hydrochlorate (11.1g, 54.5mmol) and 2,3-propylene bromide (10.9g, 54.5mmol) in methylene dichloride (200mL) solution.After 18 hours, add entry and with mixture with dichloromethane extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/5% (10% ammonium hydroxide/methyl alcohol)], obtain title compound (7.85g).

Step B:(1R)-and 1-{[(2-bromine third-2-thiazolinyl) (2,4-dimethoxy-benzyl) amino] carbonyl Base } fourth-3-alkenyl amino formic acid benzyl ester

With 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (55mg, 0.285mmol) be added to 2-bromo-N-(2, the 4-dimethoxy-benzyl) third-2-alkene-1-amine (73mg, 0.256mmol) and (2R)-the 2-{[(benzyloxy) carbonyl] amino } in methylene dichloride (5mL) solution of penta-obtusilic acid (71mg, 0.285mmol).After 18 hours, that this mixture is concentrated.Through silica gel chromatography purifying (5% ethyl acetate/hexane → 30% ethyl acetate/hexane), obtain title compound (77mg).MS?517(M+1)。

Step C:(1R)-and 1-{[[2-(2,3-difluorophenyl) third-2-thiazolinyl] 2, the 4-dimethoxy Benzyl) amino] carbonyl } fourth-3-alkenyl amino formic acid benzyl ester

Dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium methylene dichloride affixture (0.726g, 0.889mmol) be added to (1R)-1-{[(2-bromine third-2-thiazolinyl) (2, the 4-dimethoxy-benzyl) amino] carbonyl } fourth-3-alkenyl amino formic acid benzyl ester (9.2g, 17.8mmol), 2,3-difluorophenyl boric acid (2.95g, 18.7mmol) and yellow soda ash (2M in water; 19.6rnL, 39.1mmol) in the solution in DMF (60mL), and with this mixture heating up to 75 ℃.After 2 hours, this mixture makes cool to room temperature and uses dichloromethane extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (5% ethyl acetate/hexane → 55% ethyl acetate/hexane), obtain title compound (6.8g).MS?551.2(M+1)。

Step D:(3R)-and 6-(2,3-difluorophenyl)-1-(2,4-dimethoxy-benzyl)-2-oxo-2,3,4,7-tetrahydrochysene-1H-azepine -3-aminocarbamic acid benzyl ester

[1,3-two-(2,4,6-trimethylphenyl-2-imidazoles alkylidene group) dichloro (phenylmethylene)-(tricyclohexyl phosphine) ruthenium] (Grubbs two generations catalyzer) (2.62g, 3.09mmol) be added to (1R)-1-{[[2-(2, the 3-difluorophenyl) third-2-thiazolinyl] (2, the 4-dimethoxy-benzyl) amino] carbonyl } fourth-3-alkenyl amino formic acid benzyl ester (6.8g, 12.35mmol) methylene dichloride (1800mL) solution in, and this solution is heated to 40 ℃.After 48 hours, add other catalyzer (0.52g, 0.61mmol), make reaction at 40 ℃ of continuous heatings 48 hours again.Make this mixture cool to room temperature and concentrated.Through silica gel chromatography purifying (5% ethyl acetate/hexane → 55% ethyl acetate/hexane), obtain title compound (3.71g).MS?523.1(M+1)。

Step e: (3R)-6-(2,3-difluorophenyl)-oxo-2,3,4,7-tetrahydrochysene-1H-azepine

-3-aminocarbamic acid benzyl ester

Trifluoroacetic acid (60mL) is added to (3R)-6-(2,3-difluorophenyl)-1-(2,4-dimethoxy-benzyl)-2-oxo-2,3,4,7-tetrahydrochysene-1H-azepine

In the methylene dichloride of-3-aminocarbamic acid benzyl ester (3.70g, 7.08mmol) (40mL) solution.After 18 hours, this mixture is concentrated adding methyl alcohol (150mL), and filtering-depositing in 25 ℃.Filtrate is concentrated, and with methylene dichloride dilution (100mL), water (2x), saturated sodium bicarbonate aqueous solution (2x), saturated brine washing through dried over mgso, are filtered and are concentrated.Through silica gel chromatography purifying (5% ethyl acetate/hexane → 65% ethyl acetate/hexane), obtain title compound (1.75g).MS373.1(M+1)。

Step F: (3R, 6S)-6-(2,3-difluorophenyl)-2-oxa-azepan-3-base T-butyl carbamate

10% palladium charcoal (700mg) is added to (3R)-6-(2,3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydrochysene-1H-azepine

In the toluene of-3-aminocarbamic acid benzyl ester (2.6g, 6.98mmol) and tert-Butyl dicarbonate (5.03g, 23.0mmol) (200mL) solution.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 24 hours, this mixture is filtered and concentrates.Through preparation property reverse-phase chromatography purifying (DeltaPak C18,15 μ, 47mm * 300mm, 70mL/min: 80%H ₂O/NH ₄OAc: 20%CH ₃CN～100%CH ₃CN was through 60 minutes), obtain pure trans title compound (1.2g).MS341.2(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ7.07-7.04(m，2H)，6.91-6.89(m，1H)，6.04(br?s，1H)，5.93(d，J＝5.6Hz，1H)，4.46(dd，J＝10.5，4.6Hz，1H)，3.65-3.59(m，1H)，3.21(dd，J＝15.1，7.3Hz，1H)，3.05-3.00(m，1H)，2.25-2.20(m，1H)，2.17-2.10(m，2H)，1.79-1.71(m，1H)，1.46(S59H)。

Step G:(3R, 6S)-6-(2,3-difluorophenyl)-2-sulphur oxa-azepan-3- The aminocarbamic acid tert-butyl ester

Lawesson ' s reagent [2,4-two (4-p-methoxy-phenyl)-1,3-dithio-2,4-two phosphetane-2,4-disulphide] (2.90g, 7.18mmol) be added to (3R, 6S)-6-(2, the 3-difluorophenyl)-suspension of the toluene (250mL) of 2-oxa-azepan-3-aminocarbamic acid tert-butyl ester (4.79g, 14.1mmol) in, and with this mixture heating up to 90 ℃.After 1 hour, make reactant cool to room temperature and concentrated.Obtain white solid through silica gel chromatography purifying (100% methylene dichloride → 85% dichloromethane/ethyl acetate).This solid obtains title compound (4.81g) through silica gel chromatography repurity (20% ethyl acetate/hexane → 30% ethyl acetate/hexane).MS357.0(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ8.30(s，1H)，7.10-7.04(m，2H)，6.94-6.91(m，1H)，6.50(d，J＝6.1Hz，1H)，4.62(dd，J＝10.3，3.7Hz，1H)，4.13-3.88(m，1H)，3.36(dd，J＝14.7，7.1Hz，1H)，3.07(t，J＝11.2Hz，1H)，2.32-2.21(m，2H)，2.14-2.12(m，1H)，1.79-1.72(m，1H)，1.47(s，9H)。

Perhaps, (3R, 6S)-6-(2,3-difluorophenyl)-2-oxa-azepan-3-aminocarbamic acid tert-butyl ester (intermediate 28 preparation process F) can prepare according to the following step:

Step H:1-benzyl 5-methyl N, N-two (tertbutyloxycarbonyl)-D-Glu ester

Under 0 ℃, toward Boc-D-Glu-OBn (50.0g, 148.2mmol) in the solution of DCM (400ml) and MeOH (100ml) by an other funnel drip TMS two azomethanes (88.9mL 2.0M hexane solution, 117.8mmol).After 60 minutes, the concentration response thing.Resistates CH ₃CN (400mL) dilution also adds (Boc) ₂O (48.5g, 222.3mmol) then adds DMAP (18.1g, 14.8mmol).After 24 hours, reactant is concentrated and through silica gel chromatography purifying (10% → 60% ethyl acetate/hexane), obtain title compound (48.20g, 72%).MS?252.2(M+1-2Boc)。

Step I:(2R, 5E)-2-[two (tertbutyloxycarbonyl) amino]-the 6-nitro oneself-5-olefin(e) acid benzyl The base ester

Past-78 ℃ 1-benzyl 5-methyl N, the Et of N-two (tertbutyloxycarbonyl)-D-Glu ester (48.2g, 106.8mmol) ₂Slow adding DIBAL in O (400mL) mixed solution (133.4mL 1.0M toluene solution, 133.4mmol), so that internal temperature is no more than-65 ℃.After 15 minutes, add other 20mL DIBAL.Behind the restir 20 minutes, add entry (300mL) and reactant is warming to room temperature, stirred 30 minutes.This mixture is further used Et ₂O and H ₂O dilution, layering, water is with other Et ₂The O extraction.The organic extract liquid that merges is with saturated soluble tartrate sodium water solution (2x), the salt water washing through dried over mgso, is filtered and the concentrated N that obtains, N-two (tertbutyloxycarbonyl)-5-oxo-D-removes first L-valine ester (44.4g), and this product is directly used in next step.MS?444.1(M+Na)。This material is dissolved in toluene (310mL) and under 0 ℃, adds Nitromethane 99Min. (57.1mL, 1.05mol) and 1,1,3,3-tetramethyl guanidine (1.3mL, 10.5mmol).Stir after 30 minutes, the nitro aldolisation occurs fully, under 0 ℃, adds SULPHURYL CHLORIDE (12.2mL, 158mmol), then adds triethylamine (22.0mL, 158mmol), makes reactant be warming to RT.After 1 hour, add 4mL MsCl and 5.5mL triethylamine.After stirring in addition 30 minutes, this mixture Et ₂O and NaHCO ₃Dilution separates two-phase, and water layer is with other Et ₂The O backwash is washed.The organic liquor that merges is through dried over mgso, filters and concentratedly obtains resistates, and it obtains title compound (34.3g, 70%) through silica gel chromatography purifying (5% → 50% ethyl acetate/hexane).MS?487.1(M+Na)。

Step J:(5S)-and N, N-two (tertbutyloxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro -D-removes first leucine benzyl ester

With (2R, 5E)-2-[two (tertbutyloxycarbonyl) amino]-the 6-nitro oneself-5-olefin(e) acid benzyl ester (34.0g, 73.2mmol), 2,3-difluorophenyl boric acid (28.9g, 183.0mmol) and water (the solution usefulness argon-degassed in 4.62mL, the 256.2mmol) Zai diox (240mL) 15 minutes.In this solution, add sodium bicarbonate (3.08g, 36.6mmol), (S)-BINAP (1.28g, 2.05mmol) and ethanoyl acetanoto two (ethylidene) rhodium (I) (0.472g, 1.83mmol).This mixture is at 2 minutes post-heating to 35 of stirring at room ℃.After 4 hours, add 255mg (S)-BINAP and 94mg of ethanoyl acetanoto two (ethylidene) rhodium (I).After 2 hours, reactant DCM/NaHCO ₃Dilution, layering and water are washed with other DCM backwash.The organic liquor that merges is filtered and the concentrated resistates that obtains through dried over mgso, and it is through silica gel chromatography purifying (5% → 60% ethyl acetate/hexane), wherein is mixed with～title compound (37.0g, 87%) of 5%5R isomer.MS?379.1(M+1-2Boc)。

Step K: (5S)-N ² , N ² -(tertbutyloxycarbonyl)-5-(2,3-difluorophenyl)-D-relies ammonia Acid

With (5S)-N, N-(tertbutyloxycarbonyl)-5-(2, the 3-difluorophenyl)-6-nitro-D-removes first leucine benzyl ester (15.5g, 26.8mmol) and 10%Pd/C (12.0g) at EtOH (175mL, SureSeal is available from Aldrich) in solution spend the night in 55psi hydrogenation.After 18 hours, add other 4g 10%Pd/C and make this solution in again hydrogenation 18 hours of 55psi.Reactant with ethanol filtration over celite and concentrated, is obtained title compound (12.0g).MS459.2(M+1)。

Step L:(3R, 6S)-6-(2,3-difluorophenyl)-2-oxa-azepan-3-base T-butyl carbamate

Toward (5S)-N ², N ²-(tertbutyloxycarbonyl)-5-(2, the 3-difluorophenyl)-D-Lys (22.0g, 48.0mmol) DCM (700mL) solution in add EDC (11.0g, 57.6mmol) and HOAT (3.27g, 24.0mmol), then add triethylamine (10.0mL, 72.0mmol).After 60 minutes, NaHCO ₃Add, layering and water are washed with the DCM backwash.The organic liquor that merges is filtered and is concentrated through dried over mgso.This resistates obtains cyclization compound (18.0g) through silica gel chromatography purifying (10%MeOH/DCM).This compound (2.60g, 5.90mmol) of part is with DCM (60mL) dilution and add TFA (1.20mL, 11.8mmol).After 1 hour, add NaHCO ₃, layering, water is washed with the DCM backwash.The organic liquor that merges is through dried over mgso, filter also concentrated, resistates through the silica gel chromatography purifying (5% → 50%EtOAc/DCM), obtain title compound (1.14g).MS?341.1(M+1)。

Intermediate 29

[(3R, 6S)-6-(2-fluorophenyl)-2-sulphur oxa-azepan-3-yl] carboxylamine The tert-butyl ester

The synthetic method that employing is similar to intermediate 28 prepares this title compound.MS339.2(M+1)。

Intermediate 30

[(3R, 6S)-6-(2,6-difluorophenyl)-2-sulphur oxa-azepan-3-yl] amino first Tert-butyl acrylate

The synthetic method that employing is similar to intermediate 28 prepares this title compound.MS357.1(M+1)。

Intermediate 31

(3R, 6S)-6-(2,3-dichlorophenyl)-2-sulphur oxa-azepan-3-yl) amino first Tert-butyl acrylate

The synthetic method that employing is similar to intermediate 28 prepares this title compound.MS389.0(M+1)。

Intermediate 32

[(3R, 6S]-6-cyclohexyl-2-sulphur oxa-azepan-3-yl] t-butyl carbamate

Steps A: [(3R, 6S)-6-cyclohexyl-2-oxa-azepan-3-yl] amino first Tert-butyl acrylate

With platinum oxide (300mg, 1.32mmol) be added to (3R, 6S)-6-(2, the 3-difluorophenyl)-2-oxa-azepan-3-aminocarbamic acid tert-butyl ester (463mg, 1.36mmol) in the solution of Glacial acetic acid (15mL) and in the Pa Er device with the hydrogenation under 50psi hydrogen of this mixture.After 3 days, that this mixture is concentrated.Add saturated sodium bicarbonate aqueous solution, this mixture dichloromethane extraction (3x).Dried over mgso is used in the organic extract liquid salt water washing that merges, and filters and concentrates.Through silica gel chromatography purifying (hexane → 55% ethyl acetate/hexane), obtain title compound (210mg).MS?311.2(M+1)。

Step B:[(3R, 6S)-6-cyclohexyl-2-sulphur oxa-azepan-3-yl] amino T-butyl formate

With Lawesson ' s reagent [2,4-two (4-p-methoxy-phenyl)-1,3-dithio-2,4-two phosphetane-2,4-disulphide] (140mg, 0.35mmol) be added to [(3R, 65)-6-cyclohexyl-2-oxa-azepan-3-yl] t-butyl carbamate (210mg, 0.68mmol) in the suspension in toluene (8mL), and with this mixture heating up to 90 ℃.After 1 hour, make reactant cool to room temperature and concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 95% dichloromethane/ethyl acetate), obtain title compound (132mg).MS?327.2(M+1)。

Intermediate 33

3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one

Steps A: 5-cyano group-5-(2,3-difluorophenyl) Valeric acid ethylester

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 2.9g, 71.8mmol) slowly be added to (2,3-difluorophenyl) acetonitrile (10.0g, 65.3mmol) and 4-bromine fourth acetic acid (12.7g, 65.3mmol) in the solution of DMF (100mL).After 30 minutes, reaction mixture is warming to room temperature.After 3 hours, add entry also with this mixture ethyl acetate extraction (2x).The organic extract liquid saturated aqueous ammonium chloride, the saturated brine washing through dried over mgso, is filtered and the concentrated title compound that obtains.MS?267.1(M+1)。

Step B:6-amino-5-(2,3-difluorophenyl) ethyl hexanoate

With Raney nickel (2800, the diploma thing of water; With washing with alcohol (3x); 3.8g) be added in ethanol (100mL) solution of 5-cyano group-5-(2,3-difluorophenyl) Valeric acid ethylester (4.75g, 17.8mmol).Pass into ammonia in the reaction mixture and this mixture is stirred under the 48psi nitrogen atmosphere.After 18 hours, reactant is filtered and concentrates.MS?272.1(M+1)。

Step C:5-(2,3-difluorophenyl)-6-[(2, the 4-dimethoxy-benzyl) amino] caproic acid second Ester

2,4-dimethoxy benzaldehyde is added in methyl alcohol (75mL) solution of 6-amino-5-(2,3-difluorophenyl) ethyl hexanoate (4.73g, 17.5mmol).Add acetic acid until the pH of reaction mixture reaches pH 5.After 30 minutes, add sodium cyanoborohydride (1.69g, 26.9mmol).After 1 hour, this mixture dilutes with ethyl acetate and saturated aqueous sodium carbonate.This mixture ethyl acetate extraction, the organic extract liquid water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/(10% ammonium hydroxide/methyl alcohol)], obtain title compound (7.3g).MS?422.1(M+1)。

Step D:5-(2,3-difluorophenyl)-6-[(2, the 4-dimethoxy-benzyl) amino] caproic acid

With sodium hydroxide (the 1N aqueous solution; 52mL, 52.0mmol) be added to 5-(2,3-difluorophenyl)-6-[(2,4-dimethoxy-benzyl) amino] in methyl alcohol (75mL) solution of ethyl hexanoate (7.3g, 17.3mmol).1.5 after hour, this mixture is concentrated.Resistates and methylbenzene azeotropic (3x) are obtained the sodium salt of title compound.MS?394.1(M+1)。

Step e: 6-(2,3-difluorophenyl)-1-(2.4-dimethoxy-benzyl) azepan- 2-ketone

N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (3.65g, 19.1mmol) be added to 5-(2, the 3-difluorophenyl)-and 6-[(2, the 4-dimethoxy-benzyl) amino] in acetonitrile (346mL) solution of Sodium n-caproate (8.58g, 17.3mmol).After 2 hours, add hydrochloric acid (4.0M dioxane solution; 13.0mL; 52.0mmol).After 16 hours, add other N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (3.24g, 16.9mmol), I-hydroxybenzotriazole hydrate (1.0g, 6.53mmol) and triethylamine (4.83mL, 34.6mmol).After 16 hours, reaction mixture is concentrated.This mixture is with the saturated sodium bicarbonate aqueous solution dilution and use ethyl acetate extraction.Organic extract liquid washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol), obtain title compound (4.72g).MS?376.1(M+1)。

Step F: (3S, 6S)-3-allyl group-6-(2,3-difluorophenyl)-1-(2,4-dimethoxy The base benzyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2,3-difluorobenzene Base)-1-(2,4-dimethoxy-benzyl) azacycloheptan-2-one

Under-78 ℃, the lithium diisopropylamine (solution of 1.8M THF, heptane and ethylbenzene; 22.9mL, 41.3mmol) be added in tetrahydrofuran (THF) (38mL) solution of 6-(2,3-difluorophenyl)-1-(2,4-dimethoxy-benzyl) azepan-2-one (3.87g, 10.3mmol).After 1 hour, slowly add 3-bromine third-1-alkene (3.57mL, 41.3mmol).After 1 hour, reaction mixture saturated aqueous ammonium chloride termination reaction.Add saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction.Organic extract liquid washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% hexane → 70% hexane/ethyl acetate), obtain title compound (350mg).MS?416.1(M+1)。

Step G:3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one

Trifluoroacetic acid (35mL) is added to (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl)-1-(2, the 4-dimethoxy-benzyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl)-solution of 1-(2,4-dimethoxy-benzyl) azacycloheptan-2-one (3.39g, 8.15mmol) in methylene dichloride (25mL) in.2.5 after hour, reaction mixture is concentrated.Add saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction (3x).Organic extract liquid washs with saturated brine, through dried over mgso, filters and the concentrated title compound that obtains.Through silica gel chromatography purifying (98.5% methylene chloride/methanol → 97% methylene chloride/methanol), obtain racemize trans-compound (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one, and racemize cis compound (35,6R)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one and (3R, 6R)-mixture of 3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one.MS?266.1(M+1)。

Intermediate 34

N-[(3R, 6S)-6-[2, the 3-difluorophenyl]-2-sulphur oxa-azepan-3-yl]-4 -(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1- Methane amide

Steps A: (3R, 6S)-3-amino-6-(2,3-difluorophenyl) azepan-2-sulphur Ketone

Trifluoroacetic acid (5mL, 49.6mmol) is added to (3R, 6S)-6-(2,3-difluorophenyl)-2-sulphur oxa-azepan-3-aminocarbamic acid tert-butyl ester (680mg, 1.91mmol) in the solution of methylene dichloride (10mL).After 1 hour, that reactant is concentrated.Add saturated sodium bicarbonate aqueous solution and with mixture with dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound (489g).MS?257.0(M+1)。

Step B:N-[(3R, 6S)-6-(2,3-difluorophenyl)-2-sulphur oxa-azepan- The 3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) Piperidines-1-methane amide

With triethylamine (0.45mL, 3.25mmol) be added to (3R, 6S)-6-(2, the 3-difluorophenyl)-the 2-sulphur oxa-azepan-3-aminocarbamic acid tert-butyl ester (416mg, 1.62mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-formyl chloride (466mg, 1.66mmol) extremely refluxes in the solution of methylene dichloride (70mL) and with this mixture heating up.After 18 hours, make this mixture cool to room temperature and concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (685mg).MS?501.0(M+1)。

Intermediate 35

2-amino-1-cyclopropyl ethanol

Under 0 ℃, with TMS prussiate (8.68mL, 65.1mmol) and methylene dichloride (5mL) solution of zinc iodide (II) (10mg, 0.05mmol) be added drop-wise in methylene dichloride (30mL) solution of cyclopanecarboxaldehyde (4.05mL, 54.2mmol).Add complete after, this mixture is warming to room temperature.1.5 after hour, this mixture is concentrated.Under 0 ℃, with lithium aluminum hydride (1.0M diethyl ether solution; 65.1mL, 65.1mmol) be added drop-wise in ether (40mL) solution of cyclopropyl (hydroxyl) acetonitrile crude product.Add complete after, this mixture is warming to room temperature.After 1 hour, this mixture order water (2.5mL), 15% sodium hydroxide solution (2.5mL) and water (7.5mL) are processed.Polity is filtered and with washed with dichloromethane (3x), filtrate is concentrated, obtain title compound (0.79g). ¹H?NMR(500MHz，CDCl ₃)δ2.95(dd，J＝12.5，9.0Hz，1H)，2.85-2.81(m，1H)，2.73-2.69(m，1H)，1.66(br?s，2H)，0.88-0.81(m，1H)，0.56-0.47(m，1H)，0.37-0.33(m，1H)，0.24-0.20(m，1H)。

Basically according to the preparation method of intermediate 35, the intermediate of preparation table 1.

Table 1

Intermediate 44

4,4,4-, three fluoro-2-hydroxyl fourth-1-amine chlorinations

2-(2,2,2-trifluoroethyl) oxyethane (5.27g, 41.8mmol) is added to ammonia solution (2M methanol solution; 170mL, 340mmol) and this solution is heated to 60 ℃.1.25 after hour, make this mixture cool to room temperature and be concentrated into the 20mL volume.HCl (4M diox liquid; 12mL, 48mmol) slowly add and obtain white solid (4.0g) with this mixture is concentrated, its purity is 85%, wherein also comprises 15% dimerization by product.MS?144.1(M+H)。 ¹H?NMR(500MHz，CD ₃OD)δ4.17-4.12(m，1H)，3.10(dd，J＝12.9，2.9Hz，1H)，2.89(dd，J＝12.7，9.8Hz，1H)，2.50，2.35(m，2H)。

Intermediate 45

2-hydroxyl-4-methoxyl group-4-oxygen fourth-1-amine chlorination

The anhydrous salt acid gas is passed in the suspension of 4-amino-3-hydroxybutyrate (0.91g, 7.61mmol) in methyl alcohol (150mL), until this solution is saturated and in stirring at room.After 18 hours, concentrated this solution obtains title compound (1.32g).MS?134(M+1)。

Intermediate 46

2-hydroxyl-4-isopropoxy-4-oxygen fourth-1-amine chlorination

With hydrochloric acid (4.0M dioxane solution; 0.4mL, 1.6mmol) be added in Virahol (50mL) solution of 4-amino-3-hydroxybutyrate methyl esters (2.8g, 21.03mmol) and with this mixture heating up to refluxing.After 18 hours, add other hydrochloric acid (4.0M dioxane solution, 0.4mL, 1.6mmol).After 40 hours, that reaction mixture is concentrated.MS?162.1(M+1)。

Intermediate 47

2-amino-4,4,4-trifluoro fourth-1-alcohol

Steps A: 1-oxyethyl group-4,4,4-three fluoro-1-oxygen fourth-2-amine chlorinations

2-is amino-4,4, and 4-trifluoroacetic acid (11.7g, 52.8mmol) is added in ethanol (100mL) solution of saturated HCl and is heated to 85 ℃.After 4 hours, make this mixture cool to room temperature and concentrated.MS?186.0(M+1)。

Step B:2-amino-4,4,4-trifluoro fourth-1-alcohol

With lithium aluminum hydride (1M ether solution; 2.32mL, 2.32mmol) be added to 1-oxyethyl group-4,4, in ether (15mL) solution of 4-three fluoro-1-oxygen fourth-2-amine chlorinations (205mg, 0.928mmol).1.5 after hour, this mixture order water (0.085mL), 15% sodium hydroxide (0.085mL), water (0.255mL) is processed, and then filtration over celite and concentrated obtains title compound.MS?144.0(M+1)。

Intermediate 48

1-amino-3-hydroxy-3-methyl fourth-2-ketone

Steps A: (3-methyl but-2-ene-1-yl) imino-tert-Butyl dicarbonate

Potassium tert.-butoxide (52mg, 0.46mmol) is added in tetrahydrofuran (THF) (1mL) solution of imino-tert-Butyl dicarbonate (100mg, 0.46mmol).After 5 minutes, add 1-bromo-3-methyl but-2-ene (54 μ L, 0.46mmol).After 3 hours, add saturated sodium bicarbonate aqueous solution also with this mixture ethyl acetate extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.MS?286.2(M+1)。

Step B:(3-hydroxy-3-methyl-2-oxygen-butyl) iminocarbonic acid di tert butyl carbonate

Potassium permanganate (114mg, 0.72mmol) be added to (3-methyl but-2-ene-1-yl) imino-tert-Butyl dicarbonate (115mg, 0.40mmol) in the solution of acetone (0.8mL), water (0.2mL) and Glacial acetic acid (20 μ L).After 4 hours, with saturated sodium sulfite aqueous solution termination reaction.This mixture is transferred to pH 5 and uses ethyl acetate extraction (3x) with aqueous hydrochloric acid.The organic extract liquid saturated sodium bicarbonate aqueous solution that merges, the saturated brine washing through dried over mgso, is filtered and is concentrated.MS?340.1(M+Na)。

Step C:1-amino-3-hydroxy-3-methyl fourth-2-ketone

Under 0 ℃, hydrochloric acid (4M De dioxane solution; 1.0mL, 4.0mmol) be added in methyl alcohol (3mL) solution of (3-hydroxy-3-methyl-2-oxygen-butyl) imino-diacetic dimethyl dicarbonate butyl ester (102mg, 0.32mmol), and this mixture be warming to room temperature.2.5 after hour, the concentrated hydrochloride that obtains title compound of reaction mixture.MS?118.0(M+1)。

Intermediate 49

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Steps A: (3R, 6S)-6-[2,3-difluorophenyl)-and 2-[(4,4,4-, three fluoro-2-hydroxyl fourths Base) imino-] azepan-3-yl } t-butyl carbamate

Under 60 ℃, with mercury chloride (II) (2.48g, 9.12mmol) be added to [(3R, 6S)-and 6-(2,3-difluorophenyl)-2-sulphur oxa-azepan-3-yl] t-butyl carbamate (2.50g, 7.01mmol), 4,4, in 4-three fluoro-2-hydroxyl fourth-1-amine chlorinations (4.62g, 25.7mmol) and the solution of triethylamine (4.40mL, 31.6mmol) in ethanol (70mL).After 1 hour, make the reactant cool to room temperature.This mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution also with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound (3.45g).MS?466.2(M+1)。

Step B:(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

With dichromic acid pyridine (7.92g, 21.0mmol) be added to { (3R, 65)-6-(2, the 3-difluorophenyl)-2-[(4,4,4-three fluoro-2-hydroxybutyls) imino-] azepan-3-yl } in acetonitrile (70mL) solution of t-butyl carbamate crude product (3.27g, 7.01mmol).After 70 hours, this mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution also with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol), obtain title compound (2.35g).MS446.1(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ7.14-7.09(m，1H)，6.97-6.94(m，2H)，6.33(d，J＝5.8Hz，1H)，4.82(dd，J＝10.0，3.9Hz，1H)，4.12-4.07(m，1H)，3.99(d，J＝14.6Hz，1H)，3.37(q，J＝20.0，10.0Hz，2H)，2.94(t，J＝110.2Hz，1H)，2.44(d，J＝13.7Hz，1H)，2.34-2.26(m，1H)，2.16-2.13(m，1H)，1.63-1.60(m，1H)，1.57(s，9H)。

Basic according to the method for preparing intermediate 49, the intermediate of preparation table 2.In some cases, with intermediate 28 couplings in the suitable amino alcohol that uses be purchased.

Table 2

Intermediate 65

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with diisobutyl aluminium hydride (1.0M hexane liquid; 3.77mL, 3.77mmol) be added to [(6S, 9R)-9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] in methylene dichloride (12mL) solution of methyl acetate (328mg, 0.75mmol).After 1 hour, add saturated soluble tartrate sodium water solution, and with this mixture ethyl acetate extraction.Organic layer salt water washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 94% methylene chloride/methanol), obtain title compound (218mg).MS?408.1(M+1)。

Intermediate 66

2-[(6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, Acetyl Chloride 98Min. (24 μ L, 0.344mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-aminocarbamic acid the tert-butyl ester (70mg, 0.172mmol) and triethylamine (48 μ L, the 0.344mmol) solution in methylene dichloride (6mL).1.5 after hour, add saturated sodium bicarbonate aqueous solution and with mixture with dichloromethane extraction (2x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (64mg).MS?450.2(M+1)。

Intermediate 67

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-methoxy ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 4.0mg, 0.112mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In tetrahydrofuran (THF) (0.5mL) solution of-9-aminocarbamic acid tert-butyl ester (19mg, 0.047mmol) and methyl iodide (3.0 μ L, 0.051mmol), this mixture is warming to room temperature.After 18 hours, add other sodium hydride (2.0mg, 0.056mmol) and methyl iodide (3.0 μ L, 0.051mmol).After 1 hour, the water termination reaction.Add saturated sodium bicarbonate aqueous solution also with this mixture dichloromethane extraction (2x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 94% methylene chloride/methanol), obtain title compound (6mg).MS?422.1(M+1)。

Intermediate 68

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under-78 ℃, with diisobutyl aluminium hydride (1.0M dichloromethane solution; 0.81mL, 0.807mmol) be added to [(6S, 9R)-9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine

-3-yl] in methylene dichloride (10mL) solution of acetic acid isopropyl esters (187mg, 0.403mmol).After 1 hour, add other diisobutyl aluminium hydride (0.81mL, 0.807mmol).2.5 after hour, add saturated soluble tartrate sodium water solution, and with this mixture ethyl acetate extraction.The organic layer saturated sodium bicarbonate aqueous solution, the salt water washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (120mg).MS?406.2(M+1)。

Intermediate 69

(6S, 9R)-6-(2,3-difluorophenyl)-3-[2-(dimethylamino) ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Sodium cyanoborohydride (12mg, 0.185mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester (50mg, 0.123mmol) and dimethylamine (2.0M tetrahydrofuran (THF) liquid; 0.185mL, 0.370mmol) in transfer to methyl alcohol (5mL) solution of pH 5 with acetic acid.After 2 hours, that this solution is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 92% methylene chloride/methanol), obtain title compound (45mg).MS?435.2(M+1)。

Intermediate 70

(6S, 9R)-3-(2,2-, two fluoro ethyls)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, (diethylamino) sulfur trifluoride (92 μ L, 0.696mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (94mg, 0.232mmol) in methylene dichloride (10mL).After 2 hours, add saturated sodium bicarbonate aqueous solution also with this mixture dichloromethane extraction (2x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (67mg).MS?428.2(M+1)。

Intermediate 71

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxypropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Methyl-magnesium-bromide (3.0M ether solution; 0.70mL, 2.10rnmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (85mg, 0.210mmol) in tetrahydrofuran (THF) (5mL).After 2 hours, use the saturated aqueous ammonium chloride termination reaction.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (73mg).MS?422.2(M+1)。

Intermediate 72

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxy-2-methyl propyl group)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen propyl group)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with Dess-Martin reagent [1,1; 1-three (ethanoyl oxygen)-1; 1-dihydro-1,2-benziodoxol-3-(1H)-ketone] (257mg, 0.605mmol) be added to (6S; 9R)-6-(2; the 3-difluorophenyl)-3-(2-hydroxypropyl)-6,7,8; 9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (85mg, 0.202mmol) in methylene dichloride (5mL), this mixture is warming to room temperature.After 4 hours, with saturated sodium sulfite aqueous solution termination reaction.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/5% (10% ammonium hydroxide/methyl alcohol)], obtain title compound (19mg).MS?420.2(M+1)。

Step B:(6S, 9R)-6-(2,3-difluorophenyl)-3-(2-hydroxy-2-methyl propyl group)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Methyl-magnesium-bromide (3.0M ether solution; 0.49mL, 1.45mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2-oxygen propyl group)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in tetrahydrofuran (THF) (5mL) solution of t-butyl carbamate (61mg, 0.145mmol).After 2 hours, use the saturated aqueous ammonium chloride termination reaction.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol), obtain title compound (36mg).MS?436.2(M+1)。

Intermediate 73

(6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Tin anhydride (1.73g, 15.63mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester (in 2.95g, 7.82mmol) De diox (200mL) solution, and with the extremely backflow of this mixture heating up.After 8 hours, reaction mixture filters and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 40% ethyl acetate/dichloromethane), obtain title compound (2.56g).MS392.2(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ9.69(s，1H)，7.68(s，1H)，7.13-7.06(m，2H)，6.96-6.93(m，1H)，6.26(d，J＝6.1Hz，1H)，5.56(d，J＝14.2Hz，1H)，4.91(dd，J＝9.8，6.6Hz，1H)，4.13-4.08(m，1H)，3.02(t，J＝11.2Hz，1H)，2.43(d，J＝13.4Hz，1H)，2.28(dd，J＝24.5，12.1Hz，1H)，2.18-1.16(m，1H)，1.50(s，9H)。

Intermediate 74

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-, three fluoro-1-hydroxyethyls)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

With (trifluoromethyl) trimethyl silane (0.5M tetrahydrofuran (THF) liquid; 2.15mL, 1.07mmol) and tetrabutyl ammonium fluoride (1.0M tetrahydrofuran (THF) liquid; 0.107mL 0.107mmol) order adds pure (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid ester (0.14g, 0.36mmol).After 15 minutes, reaction mixture saturated sodium bicarbonate termination reaction.This mixture dichloromethane extraction (3x), and with the organic extract liquid water that merges, the saturated brine washing through dried over sodium sulfate, is filtered also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (110mg).MS?462.1(M+1)。

Intermediate 75

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-, three fluoro-1-methoxy ethyls)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 88.3mg, 2.21mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-, three fluoro-1-hydroxyethyls)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In-9-aminocarbamic acid the tert-butyl ester (0.68g, 1.47mmol) and methyl iodide (92.0 μ L, the 1.47mmol) solution in tetrahydrofuran (THF) (20mL).After 2 hours, this mixture is warming to room temperature.After 2 hours, add other methyl iodide (92.0 μ L, 1.47mmol) and sodium hydride (60% mineral oil dispersion; 10.0mg, 0.27mmol).After 1 hour, the water termination reaction is also with this mixture dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 30% ethyl acetate/dichloromethane), obtain title compound (195mg).MS?476.2(M+1)。

Intermediate 76

(6S, 9R)-6-(2,3-difluorophenyl)-3-(hydroxymethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Sodium borohydride (19.0mg, 0.51mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (100mg, 0.26mmol) (3mL) solution.After 2 hours, with reaction mixture saturated sodium bicarbonate termination reaction.Mixture dichloromethane extraction (3x), and with the organic extract liquid water that merges, the saturated brine washing through dried over sodium sulfate, is filtered also concentrated.MS?394.2(M+1)。

Intermediate 77

(6S, 9R)-6-(2,3-difluorophenyl)-3-(methoxymethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 25.0mg, 0.61mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(hydroxymethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-aminocarbamic acid the tert-butyl ester (160mg, 0.41mmol) and methyl iodide (51.0 μ L, the 0.81mmol) solution in tetrahydrofuran (THF) (2mL).After 3 hours, the water termination reaction is also with this mixture dichloromethane extraction (3x).Organic layer washes with water, and saturated brine through dried over mgso, filters and concentrates.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (75mg).MS?408.2(M+1)。

Intermediate 78

(6S, 9R)-3-(difluoromethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, (diethylamino) sulfur trifluoride (14 μ L, 0.10mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (20mg, 0.05mmol) in methylene dichloride (1mL).After 1 hour, add other (diethylamino) sulfur trifluoride (14 μ L, 0.10mmol).After 16 hours, reaction mixture saturated sodium bicarbonate termination reaction.Mixture is with dichloromethane extraction (3x), and with the organic extract liquid water that merges, the saturated brine washing through dried over sodium sulfate, is filtered and concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 7% ethanol/methylene), obtain title compound (18mg).MS?414.1(M+1)。

Intermediate 79

(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with methyl-magnesium-bromide (3.0M ether solution; 0.33mL, 1.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (130mg, 0.33mmol) (3mL) solution.After 10 minutes, the water termination reaction is also with this mixture dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.MS?408.1(M+1)。

Intermediate 80

(6S, 9R)-3-[cyclopropyl (hydroxyl) methyl]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with cyclopropyl bromination magnesium (0.5M tetrahydrofuran (THF) liquid; 1.53mL, 0.77mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (60mg, 0.15mmol) (1mL) solution.After 30 minutes, the water termination reaction is also with this mixture dichloromethane extraction (3x).Organic layer washes with water, and saturated brine through dried over mgso, filters and concentrates.MS?434.2(M+1)。

Intermediate 81

(6S, 9R)-3-[cyclopropyl (methoxyl group) methyl]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, methyl iodide (9.0 μ L, 0.15mmol) is added to (6S, 9R)-3-[cyclopropyl (hydroxyl) methyl]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester (66mg, 0.15mmol) and sodium hydride (60% mineral oil dispersion; 8.3mg, 0.23mmol) in the solution in tetrahydrofuran (THF) (1mL).After 1 hour, this mixture is warming to room temperature.After 2 hours, add other methyl iodide (6.0 μ L, 0.10mmol) and sodium hydride (60% mineral oil dispersion; 3.0mg, 0.08mmol) add.After 1 hour, the water termination reaction and with mixture with dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (23mg).MS?448.2(M+1)。

Intermediate 82

(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxymethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, methyl iodide (6.0 μ L, 0.10mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester (40mg, 0.10mmol) and sodium hydride (60% mineral oil dispersion; 6.7mg, 0.15mmol) in the solution in tetrahydrofuran (THF) (1mL).After 2 hours, this mixture is warming to room temperature.Add other methyl iodide (6.0 μ L, 0.10mmol) and sodium hydride (60% mineral oil dispersion; 2.2mg, 0.05mmol), added once in per 1.5 hours, share 4.5 hours, afterwards the water termination reaction and with mixture with dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (16mg).MS?422.2(M+1)。

Intermediate 83

(6S, 9R)-3-ethanoyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Dichromic acid pyridine (0.96g, 2.55mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene～5H-imidazo [1,2-a] azepine In the acetonitrile of-9-aminocarbamic acid tert-butyl ester (0.52g, 1.28mmol) (10mL) solution.After 18 hours, with reactant filtration over celite and concentrated.Add saturated sodium carbonate solution, and with this mixture dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 40% ethyl acetate/dichloromethane), obtain title compound (0.38g).MS?406.1(M+1)。

Intermediate 84

(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with methyl-magnesium-bromide (3.0M ether solution; 90 μ L, 0.27mmol) be added to (6S, 9R)-3-ethanoyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (22mg, 0.05mmol) (1mL) solution, and reaction mixture is warming to room temperature.After 30 minutes, the water termination reaction and with mixture with dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (15mg).MS422.2(M+1)。

Perhaps, intermediate 84 can be prepared as follows:

With 1-amino-3-hydroxy-3-methyl fourth-2-ketone (108mg, 0.70mmol) hydrochloride be added to [(3R, 6S)-6-(2, the 3-difluorophenyl)-and 2-sulphur oxa-azepan-3-yl] t-butyl carbamate (100mg, 0.28mmol) dehydrated alcohol (2.8mL) solution in, and with this mixture heating up to 60 ℃.Add mercury chloride (II) (152mg, 0.56mmol), then add immediately triethylamine (0.20mL, 1.40mmol).After 23 hours, reactant is filtered and uses methanol wash, then concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (85mg).MS?422.2(M+1)。

Intermediate 85

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-, three fluoro-1-hydroxyl-1-methylethyls)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

With (trifluoromethyl) trimethyl silane (0.273mL, 1.85mmol) and tetrabutyl ammonium fluoride (1.0M tetrahydrofuran (THF) liquid; 74 μ L, 0.074mmol) order is added to (6S, 9R)-3-ethanoyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (150mg, 0.37mmol) (1mL) solution.After 5 minutes, add other (trifluoromethyl) trimethyl silane (100 μ L, 0.678mmol) and tetrabutyl ammonium fluoride (1.0M tetrahydrofuran (THF) liquid; 25 μ L, 0.025mmol).After 30 minutes, reaction mixture saturated sodium bicarbonate termination reaction.Mixture dichloromethane extraction (3x), and with the organic extract liquid water that merges, the saturated brine washing through dried over sodium sulfate, is filtered also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (55mg).MS?476.2(M+1)。

Intermediate 86

(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

Methylsulfonic acid (77 μ L, 1.19mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In the methyl alcohol of-9-aminocarbamic acid tert-butyl ester (100mg, 0.24mmol) (5mL) solution, and with this mixture heating up to 60 ℃.After 18 hours, reaction mixture saturated sodium bicarbonate aqueous solution termination reaction.This mixture washs the organic extract liquid that merges with ethyl acetate extraction (3x) with saturated brine, through dried over sodium sulfate, filter and concentrate.MS?336.2(M+1)。

Basic according to the method for preparing intermediate 86, the intermediate of preparation table 3.

Table 3

Intermediate 94

(6S, 9R)-9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-methyl-formiate

Steps A: (6S, 9R)-9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-formic acid

SODIUM PHOSPHATE, MONOBASIC (127mg, 0.92mmol) and Textone (42mg, 0.46mmol) are added to (6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (45mg, 0.12mmol) in tetrahydrofuran (THF) (0.8mL), water (0.8mL), the trimethyl carbinol (0.2mL) and 2-methyl-2-butene (0.2mL).After the vigorous stirring 3 hours, reaction mixture saturated ammonium chloride solution termination reaction.This mixture is with ethyl acetate extraction (3x), and with the organic extract liquid water that merges, the saturated brine washing through dried over sodium sulfate, is filtered and concentrated.MS?408.1(M+1)。

Step B:(6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -3-methyl-formiate

With (TMS) two azomethanes (2.0M ether solution; 173 μ L, 0.35mmol) be added to (6S, 9R)-9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-3-formic acid (47mg, 0.12mmol) in methylene dichloride (1.5mL) and methyl alcohol (0.5mL).After 1 hour, add other (TMS) two azomethanes (2.0M ether solution; 50 μ L, 0.10mmol).After 4 hours, that reaction mixture is concentrated.MS?422.2(M+1)。

Intermediate 95

[(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Under 0 ℃, with ethylmagnesium bromide (3M ether solution; 0.17mL, 0.51mmol) be added drop-wise to Virahol (IV) titanium (0.08mL, 0.26mmol) and (6S through 15 minutes, 9R)-and the 9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine

In the ether of-3-methyl-formiate (54mg, 0.13mmol) (0.9mL) solution.1.5 after hour, add other Virahol (IV) titanium (0.08mL, 0.26mmol) and ethylmagnesium bromide (3M ether solution; 0.17mL, 0.51mmol).1.5 after hour, this mixture is with the saturated sodium bicarbonate aqueous solution termination reaction and use ethyl acetate extraction (3x).The organic layer that merges washs with saturated brine, uses dried over mgso, filters and concentrates.Through reversed-phase HPLC purifying (C-18,80% water/acetonitrile → 40% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (23mg).MS?420.2(M+1)。

Intermediate 96

[(6S, the 9R)-3-tertiary butyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

The 9-yl] t-butyl carbamate

Under 70 ℃, with mercury chloride (II) (10mg, 0.036mmol) be added to [(3R, 6S)-6-(2, the 3-difluorophenyl)-and 2-sulphur oxa-azepan-3-yl] t-butyl carbamate (10mg, 0.028mmol), 1-be amino-3, the hydrobromate (11mg of 3-dimethyl butyrate-2-ketone, 0.056mmol) and the solution of triethylamine (10 μ L, 0.07mmol) in ethanol (1mL) in.After 18 hours, make the reactant cool to room temperature.This mixture is filtered and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (14mg).MS?420.2(M+1)。

Intermediate 97

[(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methyl-propyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Under 0 ℃, with ethylmagnesium bromide (3.0M ether solution; 82.0 μ L, 0.247rnmol) be added to (6S, 9R)-3-ethanoyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In the tetrahydrofuran (THF) of-9-aminocarbamic acid tert-butyl ester (25mg, 0.062mmol) (1mL) solution.After 10 minutes, reaction mixture water termination reaction is also with this mixture dichloromethane extraction (3x).The organic layer water, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 60% dichloromethane/ethyl acetate), obtain title compound (17mg).MS?436.2(M+1)。

Intermediate 98 and intermediate 99

[(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate and [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-ethyl-1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Under 0 ℃, ethylmagnesium bromide (3M ether solution; 0.32mL, 0.95mmol) be added drop-wise to Virahol (IV) titanium (0.141mL, 0.475mmol) and (6S, 9R)-and the 9-[(tertbutyloxycarbonyl) amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine

In the solution of-3-methyl-formiate (100mg, 0.237mmol) in tetrahydrofuran (THF) (4mL).After 40 minutes, add other Virahol (IV) titanium (0.141mL, 0.475mmol) and ethylmagnesium bromide (3M ether solution; 0.316mL, 0.95mmol).After 40 minutes, add again other ethylmagnesium bromide (3M ether solution; 0.316mL, 0.95mmol) add.After 40 minutes, this mixture is with saturated aqueous ammonium chloride and saturated sodium bicarbonate aqueous solution termination reaction, and with ethyl acetate extraction (3x).The organic layer that merges washs with saturated brine, uses dried over mgso, filters and concentrates.Obtain [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine through silica gel chromatography purifying (100% methylene dichloride → 95% dichloromethane/ethyl acetate)

-9-yl] t-butyl carbamate (62mg) MS420.2 (M+1) and [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-ethyl-1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] mixture of t-butyl carbamate (18mg) MS 450.2 (M+1).

Intermediate 100

[(6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Steps A: { (2Z, 3R, 6S)-6-(2,6-difluorophenyl)-2-[(4,4,4-, three fluoro-2-hydroxyls The base butyl) imino-] azepan-3-yl } t-butyl carbamate

Under 55 ℃, with mercury chloride (II) (538mg, 1.98mmol) be added to [(3R, 6S)-and 6-(2,6-difluorophenyl)-2-sulphur oxa-azepan-3-yl] t-butyl carbamate (353mg, 0.99mmol), 4,4, in 4-three fluoro-2-hydroxyl fourth-1-amine chlorinations (498mg, 2.77mmol) and the solution of triethylamine (0.61mL, 4.36mmol) in ethanol (10mL).After 2 hours, make the reactant cool to room temperature.This mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (2x).The organic extract liquid that merges filters and the concentrated title compound that obtains through dried over mgso.MS?466.2(M+1)。

Step B:[(6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

With dichromic acid pyridine (2.24g, 5.94mmol) be added to { (2Z, 3R, 6S)-6-(2, the 6-difluorophenyl)-2-[(4,4,4-, three fluoro-2-hydroxybutyls) imino-] azepan-3-yl } in acetonitrile (20mL) solution of t-butyl carbamate (461mg, 0.99mmol).After 18 hours, this mixture filters and is concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (80% hexane/ethyl acetate → 50% hexane/ethyl acetate), obtain title compound.MS?446.2(M+1)。

Basic according to the method for preparing intermediate 100, the intermediate of preparation table 4.

Table 4

Intermediate 103

2-{1-[(6S, 9R)-9-amino-6-(2,6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-the 1-methyl ethoxy } ethanol

Methylsulfonic acid (78 μ L, 1.19mmol) is added to [(6S, 9R)-6-(2,6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine

-9-yl] in ethylene glycol (4mL) solution of t-butyl carbamate (104mg, 0.24mmol), and with this mixture heating up to 60 ℃.After 18 hours, reaction mixture is concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x), the organic extract liquid that merges is washed with saturated brine, through dried over sodium sulfate, filter also concentrated.MS366.1(M+1)。

Intermediate 104

2-[(6S, 9R)-9-amino-6-(2,6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-propan-2-ol

According to the method for preparing intermediate 103 descriptions, water replaces ethylene glycol to prepare intermediate 104.MS?322.1(M+1)。

Intermediate 105

[(6S, 9R)-6-(2-fluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Substantially according to the method preparation for preparing intermediate 100 descriptions.MS?428.2(M+1)。

Intermediate 106

[(6S, 9R)-6-cyclohexyl-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Substantially according to the method preparation for preparing intermediate 100 descriptions.MS?416.3(M+1)。

Intermediate 107

[(6S, 9R)-6-(2,3-difluorophenyl)-3-ethyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Substantially according to the method preparation for preparing intermediate 100 descriptions.MS?424.1(M+1)。

Intermediate 108

(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-aminocarbamic acid the tert-butyl ester

Steps A: (3R, 6S)-6-(2,3-difluorophenyl)-2-hydrazine is pitched basic azepan-3- The aminocarbamic acid tert-butyl ester

One hydrazine hydrate (2.23mL, 46.0mmol) is added in methyl alcohol (25mL) solution of (3R, 6S)-6-(2,3-difluorophenyl)-2-sulphur oxa-azepan-3-aminocarbamic acid tert-butyl ester (546mg, 1.53mmol).After 30 minutes, that this mixture is concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates, and obtains title compound (548mg).MS?355.2(M+1)。

Step B:(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester

With triethylamine (0.259mL, 1.86mmol) be added to (3R, 65)-6-(2, the 3-difluorophenyl)-the 2-hydrazine pitches the basic azepan-3-aminocarbamic acid tert-butyl ester (548mg, 1.55mmol), 3,3,3-trifluoroacetic acid (0.205mL, 2.32mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (356mg, 1.86mmol) and the solution of 1-hydroxyl-7-azepine benzotriazole (253mg, 1.86mmol) in methylene dichloride (55mL) in.After 18 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol), obtain title compound (618mg).MS?447.1(M+1)。

Basic according to the method for preparing intermediate 108, the intermediate of preparation table 5.

Table 5

Intermediate 112

[6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] acetic acid

Steps A: 3-allyl group-6-(2,3-difluorophenyl) azepan-2-thioketones

With Lawesson ' s reagent [2,4-two (4-p-methoxy-phenyl)-1,3-dithio-2,4-two phosphetane-2,4-disulphide] (649mg, 1.61mmol) be added in the suspension of 3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one (426mg, 1.61mmol) in toluene (10mL).After 3 hours, reaction mixture is heated to 45 ℃.After 30 minutes, that this mixture is concentrated in cooling bath.Through silica gel chromatography purifying (100% hexane → 70% hexane/ethyl acetate), obtain title compound (257mg).MS?282.1(M+1)。

Step B:(2Z)-3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one hydrazone

Hydrazine is (anhydrous; 1.11mL, 35.40mmol) be added in ethanol (8mL) solution of 3-allyl group-6-(2,3-difluorophenyl) azepan-2-thioketones (249mg, 0.885mmol).After 4 hours, that reaction mixture is concentrated.Resistates is with saturated sodium bicarbonate aqueous solution dilution and with dichloromethane extraction (3x).Organic extract liquid is dry through S-WAT, filters and the concentrated title compound that obtains.(MS?280.2(M+1)。

Step C:9-allyl group-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

With triethylamine (142 μ L, 1.02mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (196mg, 1.02mmol) and 1-hydroxyl-7-azepine benzotriazole (139mg, 1.02mmol) be added to (2Z)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one hydrazone (285mg, 1.02mmol) and 3,3, in the solution of 3-trifluoroacetic acid (90 μ L, 1.02mmol) in acetonitrile (25mL).After 18 hours, add other triethylamine (0.14mL, 1.02mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (100mg, 0.52mmol), 1-hydroxyl-7-azepine benzotriazole (70mg, 0.51mmol) and 3,3,3-trifluoroacetic acid (45 μ L, 0.51mmol).5.5 after hour, reaction mixture is heated to 60 ℃.2.5 after hour, make this mixture be cooled to room temperature.After 18 hours, reaction mixture is diluted with ethyl acetate and saturated sodium bicarbonate aqueous solution.This mixture ethyl acetate extraction with the saturated brine washing, through dried over sodium sulfate, filters and concentrates.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (275mg).MS?372.1(M+1)。

Step D:[6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] acetic acid

Sodium periodate (191mg, 0.89mmol) in water (7.77mL) is added to 9-allyl group-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

In the tetrahydrofuran (THF) of (83mg, 0.224mmol) (7mL) solution.With yellow soda ash (0.5M; 0.20mL) reaction mixture is transferred to pH 7.5 and adds potassium permanganate (7mg, 0.045mmol).3.5 after hour, add other potassium permanganate (7mg, 0.045mmol) and salt of wormwood (0.20mL).After 18 hours, add the saturated sodium sulfite aqueous solution and methylene dichloride, and with hydrochloric acid the pH of solution is transferred to pH 5.This mixture dichloromethane extraction (5x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains the hydrochloride of title compound.MS?390.1(M+1)。

Substantially the method for preparing according to intermediate 112, the intermediate of preparation table 6.After step B, step C or the step D, can prepare cis and trans diastereomer by reverse-phase chromatography.

Table 6

Embodiment 1

N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-sec.-propyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Steps A: N-{ (3R, 6S)-6-(2,3-difluorophenyl)-2-[(2-hydroxy-3-methyl Butyl) imino-] azepan-3-yl }-4-(2-oxo-2,3-dihydro-1H-miaow Azoles is [4,5-b] pyridine-1-yl also) piperidines-1-methane amide

Under 55 ℃, with mercury chloride (II) (85mg, 0.314mmol) be added to N-[(3R, 6S)-6-(2, the 3-difluorophenyl)-2-sulphur oxa-azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide (105mg, 0.210mmol) in methyl alcohol (7mL) solution of and 1-amino-3-methyl fourth-2-alcohol (122mg, 1.18mmol).After 1 hour, make the reactant cool to room temperature.This mixture is filtered and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (164mg) of trifluoroacetic acid salt form.MS?570.2(M+1)。

Step B:N-{ (3R, 6S)-6-[2, the 3-difluorophenyl)-3-sec.-propyl-6,7,8,9-tetrahydrochysene-H-imidazo [1,2-a] azepine -9-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

With Dess-Martin reagent [1; 1; 1-three (ethanoyl oxygen)-1; 1-dihydro-1; 2-benziodoxol-3-(1H)-ketone] (174mg; 0.411mmol) be added to N-{ (3R; 6S)-6-(2; the 3-difluorophenyl)-and 2-[(2-hydroxy-3-methyl butyl) imino-] azepan-3-yl }-4-(2-oxo-2; 3-dihydro-1H-imidazo [4; 5-b] pyridine-1-yl) in the trifluoroacetate (164mg, 0.206mmol) and the solution of acetic acid (24 μ L, 0.411mmol) in methylene dichloride (10mL) of piperidines-1-methane amide.After 1 hour, add S-WAT (100mg, 0.793mmol) and ethanol (10mL) also with this mixture heating up to 80 ℃.After 1 hour, make reactant cool to room temperature and concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride/methanol)], obtain title compound (76mg).MS?550.2748(M+1)。

Basic preparation method according to embodiment 1, the embodiment compound in the preparation table 7.

Table 7

Embodiment 10

N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 3mL, 12.0mmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in Isosorbide-5-Nitrae-dioxs (3mL) solution of t-butyl carbamate (113mg, 0.261mmol).2.5 after hour, reactant is concentrated, obtains the title compound (117mg) of dihydrochloride form.MS?334.2(M+1)。

Step B:N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (43 μ L, 0.310mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the dihydrochloride (42mg, 0.103mmol) of-9-amine and 4-chloroformate nitrophenyl ester (21mg, the 104mmol) solution in tetrahydrofuran (THF) (3mL).After 30 minutes, add 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-dichloride (45mg, 0.155mmol), triethylamine (43 μ L, 0.310mmol) and methylene dichloride (3mL), and make this mixture be warming to room temperature.After 18 hours, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (35mg).MS?578.2702(M+1)。Basic preparation method according to embodiment 10, the embodiment compound in the preparation table 8.

Table 8

Embodiment 47

N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine-1-methane amide

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 4.0mL, 16.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester is (in 100mg, 0.224mmol) De diox (2mL) solution.After 1 hour, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?346.1(M+1)。

Step B:N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine-1-methane amide

Under 0 ℃, triethylamine (94 μ L, 0.673mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (94mg, 0.224mmol) and 4-chloroformate nitrophenyl ester (45mg, the 0.224mmol) solution in tetrahydrofuran (THF) (3mL).After 1 hour, adding 2 '-oxo-1 ', 2 '-the dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (62mg, 0.224mmol) and triethylamine (94 μ L, 0.673mmol), and make this mixture be warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride/methanol], obtain title compound (62mg).MS?575.2179(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ8.33(s，1H)，8.18(dd，J＝5.1，1.5Hz，1H)，7.56(dd，J＝7.6，1.5Hz，1H)，7.15-7.12(m，2H)，7.02-6.98(m，2H)，6.95(s，1H)，6.62(d，J＝3.4Hz，1H)，5.05(dd，J＝9.5，4.9Hz，1H)，4.16(J＝13.8，10.6Hz，1H)，4.03(d，J＝14.7Hz，1H)，3.40-3.93(m，2H)，3.84-3.72(m，2H)，3.41(dd，J＝19.9，9.9Hz，2H)，2.99(t，J＝11.7Hz，1H)，2.56-2.53(m，1H)，2.39-2.34(m，1H)，2.20-2.17(m，1H)，2.04-2.01(m，2H)，1.93-1.58(m，2H)。

Basic preparation method according to embodiment 47, the embodiment compound in the preparation table 9.

Table 9

Embodiment 61

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(2-hydroxyethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-the 1-methane amide

Under 0 ℃, triethylamine (14 μ L, 0.104mmol) is added to 2-{1-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -3-yl]-the 1-methyl ethoxy } in ethanol (38mg, 0.104mmol) and the solution of 4-chloroformate nitrophenyl ester (21mg, 0.104mmol) in tetrahydrofuran (THF) (3mL).After 1 hour, add 1 '-methylspiro [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone (23mg, 0.104mmol) and triethylamine (42 μ L, 0.31mmol), and this mixture is warming to room temperature.After 16 hours, add saturated aqueous sodium carbonate also with this mixture ethyl acetate extraction (3x).Organic layer washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 92% methylene chloride/methanol), obtain title compound (41mg).MS?609.3013(M+1)。

Embodiment 62

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-amine

Trifluoroacetic acid (2mL) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (50mg, 0.112mmol) in methylene dichloride (2mL).After 1 hour, add saturated sodium bicarbonate aqueous solution.Mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over sodium sulfate, filter and concentrate.MS?346.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Under 0 ℃, triethylamine (16 μ L, 0.11mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In-9-amine (38mg, 0.11mmol) and 4-chloroformate nitrophenyl ester (23mg, the 0.11mmol) solution in tetrahydrofuran (THF) (2mL).After 1 hour, the adding spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (25mg, 0.11mmol) and triethylamine (47 μ L, 0.33mmol), and make this mixture be warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (46mg).MS591.2132(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ9.07(s，1H)，8.33(dd，J＝4.9，1.5Hz，1H)，7.46(d，J＝7.0Hz，1H)，7.15-7.11(m，2H)，7.08(dd，J＝7.6，4.9Hz，1H)，7.01-6.99(m，1H)，6.96(s，1H)，6.62(d，J＝5.1Hz，1H)，5.32-5.00(m，1H)，4.17-4.12(m，2H)，4.10-4.07(m，1H)，4.03(d，J-14.7Hz，1H)，3.51(dd，J＝25.2，12.5Hz，2H)，3.41(dd，J＝19.9，9.9Hz，2H)，2.98(t，J＝11.2Hz，1H)，2.53-2.49(m，1H)，2.38-2.35(m，1H)，2.21-2.18(m，3H)，2.09-1.97(m，2H)，1.61-1.59(m，1H)。

Embodiment 63

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (52 μ L, 0.38mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-amine (0.14g, 0.42mmol) and 4-chloroformate nitrophenyl ester (93mg, 0.46mmol) in tetrahydrofuran (THF) (10mL).After 30 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (101mg, 0.46mmol) and triethylamine (126 μ L, 1.25mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (149mg).MS?581.2657(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ8.68(s，1H)，8.31(d，J＝5.1Hz，1H)，7.45(d，J＝7.6Hz，1H)，9.29-7.07(m，3H)，6.99-6.97(m，1H)，6.78(s，1H)，6.65(d，J＝4.9Hz，1H)，5.01(dd，J＝10.3，4.2Hz，1H)，4.89(d，J＝14.4Hz，1H)，4.15-4.08(m，3H)，3.53-3.48(m，2H)，3.07(s，3H)，3.03(t，J＝11.1Hz，1H)，2.48(d，J＝13.2Hz，1H)，2.31-2.29(m，1H)，2.21-2.18(m，2H)，2.13-2.11(m，1H)，2.08-1.97(m，2H)，1.60(br?s，1H)，1.54(s，3H)，1.52(s，3H)。

Embodiment 64

Steps A: 2-[(6S, 9R)-and 9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] propan-2-ol

Trifluoroacetic acid (2mL, 26.9mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] in the solution of t-butyl carbamate (100mg, 0.24mmol) in methylene dichloride (3mL).After 1 hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.MS?322.2(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (31 μ L, 0.23mmol) is added to 2-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] in propan-2-ol (76mg, 0.24mmol) and the solution of 4-chloroformate nitrophenyl ester (50mg, 0.25mmol) in tetrahydrofuran (THF) (3mL).After 20 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (57mg, 0.26mmol) and triethylamine (99 μ L, 0.71mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).Organic extract liquid washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (92mg).MS567.2534(M+1)。 ¹H?NMR(500MHz，CDCl ₃)δ8.27(dd，J＝5.4，1.5Hz，1H)，7.88(dd，J＝7.7，1.6Hz，1H)，7.36(s，1H)，7.26-7.22(m，3H)，5.37-5.32(m，2H)，4.65(dd，J＝14.4，10.5Hz，1H)，4.26(d，J＝13.2Hz，1H)，4.15(d，J＝13.9Hz，1H)，3.51-3.46(m，1H)，3.41-3.35(m，1H)，3.33-3.27(m，2H)，2.42-2.36(m，1H)，2.29-2.27(m，1H)，2.2，3-2.19(m，4H)，2.17-2.09(m，1H)，1.62(s，3H)，1.60(s，3H)。

Basic preparation method according to embodiment 62-64, the embodiment compound in the preparation table 10.

Table 10

Embodiment 95

N-{ (6S, 9R)-3-(1-amino-ethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Steps A: [(6S, 9R)-3-{ (E)-[tertiary butyl sulfinyl (imino-) methyl] }-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate

Titanium ethanolate (IV) (239mg, 1.05mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate (205mg, 0.524mmol) and (the R)-solution of 2-methylpropane-2-thionyl amines (79mg, 0.655mmol) in tetrahydrofuran (THF) (8mL).Reaction mixture is heated to 60 ℃.After 6 hours, make the reaction mixture cool to room temperature.Add saturated sodium bicarbonate, and with this mixture dichloromethane extraction (3x).The organic extract liquid dried over mgso is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride/methanol), obtain title compound (252mg).MS?495.2(M+1)。

Step B:[(6S, 9R)-3-{1-[(tertiary butyl sulfinyl) amino] ethyl }-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] t-butyl carbamate

Under 0 ℃, methyl-magnesium-bromide (0.24mL, 0.71mmol) is added to [(6S; 9R)-3-{ (E)-[tertiary butyl sulfinyl (imino-) methyl] }-6-(2,3-difluorophenyl)-6,7; 8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in the solution of tetrahydrofuran (THF) (4mL) of t-butyl carbamate (117mg, 0.24mmol).After 5 minutes, make this mixture be warming to room temperature.1.5 after hour, add other methyl-magnesium-bromide (0.24mL, 0.71mmol).1.5 after hour, reaction mixture is cooled to 0 ℃ also with saturated aqueous ammonium chloride and water termination reaction.This mixture ethyl acetate extraction (3x).Organic extract liquid washs with saturated brine, uses dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 94% methylene chloride/methanol), obtain title compound (144mg).MS?511.2(M+1)。

Step C:N-{1-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-2-methylpropane-2-sulfinyl amine

Trifluoroacetic acid (1mL, 13.5mmol) is added to [(6S, 9R)-3-{1-[(tertiary butyl sulfinyl) amino] ethyl }-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in the solution of t-butyl carbamate (144mg, 0.28mmol) in methylene dichloride (5mL).1.5 after hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges washs with saturated brine, through dried over mgso, filters and concentrates.MS?411.1(M+1)。

Step D:N-{ (6S, 9R)-3-{1-[(tertiary butyl sulfinyl) imino-] ethyl }-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (14 μ L, 0.097mmol) is added to N-{1-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] ethyl-2-methylpropane-2-sulfinyl amine (40mg, 0.097mmol) and the solution of 4-chloroformate nitrophenyl ester (20mg, 0.097mmol) in tetrahydrofuran (THF) (3mL) in.After 10 minutes, the adding spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (hydrochloride (43mg, 0.146mmol) of 1 ' H)-ketone and triethylamine (28 μ L, 0.194mmol), and make this mixture be warming to room temperature.1.5 after hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).Organic extract liquid washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (65mg).MS?656.3(M+1)。

Step e: N-{ (6S, 9R)-3-(1-amino-ethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Hydrochloric acid (4.0M diox liquid; 0.50mL, 2.0mmol) be added to N-[(6S, 9R)-3-{1-[(tertiary butyl sulfinyl) amino] ethyl }-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-methyl alcohol (7mL) solution of pyrido [2,3-d] [1,3] oxazine]-1-methane amide (65mg, 0.099mmol) in.After 16 hours, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (C-18,100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (44mg).MS?552.2558(M+1)。

Embodiment 96

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(dimethylamino) ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Sodium cyanoborohydride (5.0mg, 0.080mmol) is added to N-{ (6S, 9R)-3-(1-amino-ethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide (15mg, 0.023mmol) and formaldehyde (37% methanol solution; 27 μ L, 0.363mmol) in methyl alcohol (1mL) solution.After 16 hours, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (15mg).MS?580.2858(M+1)。

Embodiment 97

N-{ (6S, 9R)-3-(1-amino-1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Steps A: (6S, 9R)-3-(1-azido--1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

Methylsulfonic acid (0.30mL, 4.63mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in t-butyl carbamate (50mg, 0.115mmol) and the solution of sodiumazide (170mg, 2.62mmol) in chloroform (10mL).After 1 hour, add other methylsulfonic acid (0.95mL, 14.65mmol).After 16 hours, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (38mg).MS?347.1(M+1)。

Step B:N-{ (6S, 9R)-3-(1-azido--1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (15 μ L, 0.11mmol) is added to (6S, 9R)-3-(1-azido--1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (38mg, 0.11mmol) and 4-chloroformate nitrophenyl ester (22mg, the 0.11mmol) solution in tetrahydrofuran (THF) (5mL).After 30 minutes, add other 4-chloroformate nitrophenyl ester (5mg, 0.025mmol).After 10 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (hydrochloride (50mg, 0.171mmol) of 1 ' H)-ketone and triethylamine (40 μ L, 0.287mmol), and this mixture is warming to room temperature.After 16 hours, add saturated aqueous sodium carbonate also with this mixture ethyl acetate extraction (3x).Organic extract liquid, filters and concentrates through dried over mgso with the washing of washing saturated brine.Through silica gel chromatography purifying (100% methylene dichloride → 92% methylene chloride/methanol), obtain title compound (37mg).MS?592.2(M+1)。

Step C:N-{ (6S, 9R)-3-(1-amino-1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Palladium (10% palladium charcoal; 10mg) be added to N-[(6S, 9R)-3-(1-azido--1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-ethyl acetate (5mL) solution of pyrido [2,3-d] [1,3] oxazine]-1-methane amide (37mg, 0.063mmol) in.Reaction vessel is degassed and recharge nitrogen (3x), then recharge hydrogen (1 normal atmosphere).After 3 hours, add methyl alcohol (5mL).After 18 hours, this mixture is filtered and concentrates.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound.MS?566.2725(M+1)。

Embodiment 98

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(dimethylamino) ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Sodium cyanoborohydride (6.0mg, 0.093mmol) is added to N-[(6S, 9R)-3-(1-amino-1-methylethyl)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-hydrochloride (18mg, 0.027mmol) and formaldehyde (37% methanol solution of pyrido [2,3-d] [1,3] oxazine]-1-methane amide; 32 μ L, 0.427mmol) in the solution in methyl alcohol (1.5mL).After 1 hour, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (14mg).MS594.2992(M+1)。

Embodiment 99

2-[1-((6S, 9R)-6-(2,3-difluorophenyl)-9-{[(2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine-1-yl) carbonyl] amino }-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl)-and the 1-methyl ethoxy] ethylhexoate

Under 0 ℃, triethylamine (28 μ L, 0.20mmol) is added to N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-1-methane amide (61mg, 0.10mmol) and the solution of Acetyl Chloride 98Min. (14.0 μ L, 0.204mmol) in methylene dichloride (5mL) in.After 45 minutes, add other Acetyl Chloride 98Min. (7.0 μ L, 0.102mmol) and triethylamine (14 μ L, 0.10mmol).After 20 minutes, add again other Acetyl Chloride 98Min. (5.0 μ L, 0.07mmol).After 1 hour, reaction mixture water termination reaction.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (2x).The organic extract liquid dried over mgso is filtered and is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (35mg).MS?653.2920(M+1)。

Embodiment 100

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide steps A: N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-1 '-(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Under 0 ℃, triethylamine (18 μ L, 0.126mmol) is added to 2-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] in propan-2-ol (45mg, 0.140mmol) and the solution of 4-chloroformate nitrophenyl ester (31mg, 0.154mmol) in tetrahydrofuran (THF) (4mL).After 1 hour, adding 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (41mg, 0.154mmol) and triethylamine (39 μ L, 0.378mmol), and this mixture is warming to room temperature.After 3 hours, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride/methanol], obtain title compound (69mg).MS?611.2780(M+1)。

Embodiment 101

-9-yl }-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Steps A: N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl] in propan-2-ol (45mg, 0.140mmol) and the solution of 4-chloroformate nitrophenyl ester (31mg, 0.154mmol) in tetrahydrofuran (THF) (4mL).After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (41mg, 0.154mmol) and triethylamine (39 μ L, 0.378mmol), and this mixture is warming to room temperature.After 3 hours, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride/methanol], obtain title compound (69mg).MS?581.2690(M+1)。

Basic preparation method according to embodiment 101, the embodiment compound in the preparation table 11.

Table 11

Embodiment 104

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-4-(8-oxo-8,9-dihydro-7H-purine-7-yl) piperidines-1-methane amide

-9-amine

Hydrochloric acid (4.0M diox liquid; 2.0rnL, the te7 tertiary butyl (6S, 9R)-6-in the solution that 8.0mmol) is added to (2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid ester (100mg, 0.224mmol) in diox (1mL).After 1 hour, the concentrated hydrochloride that obtains title compound of reaction mixture.MS?346.1(M+1)。

-9-yl }-4-(8-oxo-8,9-dihydro-7H-purine-7-yl) piperidines-1-methane amide

In-9-amine hydrochlorate (94mg, 0.224mmol) and 4-chloroformate nitrophenyl ester (45mg, the 0.224mmol) solution in tetrahydrofuran (THF) (3mL).After 1 hour, add 8-oxo-7-piperidin-4-yl-8,9-dihydro-7H-purine-3-dichloride (66mg, 0.224mmol) and triethylamine (94 μ L, 0.673mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (76mg).MS?591.2214(M+1)。

Basic preparation method according to embodiment 104, the embodiment compound in the preparation table 12.

Table 12

Embodiment 109

-9-yl }-4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Hydrochloric acid (4.0M diox liquid; 2.0mL, 8.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester is (in 20mg, 0.045mmol) De diox (1mL) solution.After 1 hour, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.1(M+1)。

Under 0 ℃, triethylamine (19 μ L, 0.135mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (18.8mg, 0.045mmol) and 4-chloroformate nitrophenyl ester (9.0mg, the 0.045mmol) solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 6-fluoro-2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-δ] pyridine-4-dichloride (14mg, 0.045mmol) and triethylamine (19 μ L, 0.135mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (12.5mg).MS?608.2229(M+1)。

Embodiment 110

-9-yl }-4-(5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl) piperidines-1-methane amide

Hydrochloric acid (4.0M diox liquid; 2.0mL, 8.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-aminocarbamic acid the tert-butyl ester is (in 20mg, 0.045mmol) De diox (1mL) solution.After 1 hour, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?346.1(M+1)。

In-9-amine hydrochlorate (18.8mg, 0.045mmol) and 4-chloroformate nitrophenyl ester (9.0mg, the 0.045mmol) solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 5-phenyl-2-piperidin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-ketone (11mg, 0.045mmol) and triethylamine (19 μ L, 0.135mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (11mg).MS?616.2509(M+1)。

Embodiment 111

-9-aminocarbamic acid the tert-butyl ester is (in 20mg, 0.045mmol) De diox (1mL) solution.After 1 hour, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?346.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-4-(5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl) piperidines-1-methane amide

In-9-amine hydrochlorate (18.8mg, 0.045mmol) and 4-chloroformate nitrophenyl ester (9.0mg, the 0.045mmol) solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 3-piperidin-4-yl-3,4-dihydroquinazoline-2 (1H)-ketone (10mg, 0.045mmol) and triethylamine (19 μ L, 0.135mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (7.8mg).MS?603.2536(M+1)。

Embodiment 112

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-4-(2-oxo-Isosorbide-5-Nitrae-dihydroquinazoline-3 (2H)-1-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (5.0 μ L, 0.037mmol) is added to 2-{1-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-the 1-methyl ethoxy } in ethanol (15.0mg, 0.041mmol) and the solution of 4-chloroformate nitrophenyl ester (9.0mg, 0.045mmol) in tetrahydrofuran (THF) (1mL).After 15 minutes, add 3-piperidin-4-yl-3,4-dihydroquinazoline-2 (1H)-ketone (9.0mg, 0.041mmol) and triethylamine (17 μ L, 0.12mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).Organic layer washs with saturated brine, through dried over mgso, filters and concentrates.Through reversed-phase HPLC purifying (95% water/acetonitrile → 5% water/acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (8.5mg).MS?623.3163(M+1)。

Embodiment 113

-9-yl }-4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-methane amide

-9-amine

In the solution of-9-aminocarbamic acid tert-butyl ester (50mg, 0.112mmol) in methylene dichloride (2mL).After 1 hour, add saturated sodium bicarbonate aqueous solution.This mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over sodium sulfate, filter and concentrate.MS?346.1(M+1)。

-9-yl }-4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (16 μ L, 0.11mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (38mg, 0.11mmol) and 4-chloroformate nitrophenyl ester (23mg, the 0.11mmol) solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 1-piperidin-4-yl imidazolidine-2,4-dione (21mg, 0.11mmol) and triethylamine (47 μ L, 0.33mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride/methanol], obtain title compound (36mg).MS?555.2126(M+1)。

Basic preparation method according to embodiment 113, the embodiment compound in the preparation table 13.

Table 13

Embodiment 120

-9-yl }-2-oxo-2,3-dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-methane amide

-9-amine

In the solution of-9-aminocarbamic acid tert-butyl ester (50mg, 0.112mmol) in methylene dichloride (2mL).After 1 hour, add saturated sodium bicarbonate aqueous solution.This mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over sodium sulfate, filter and concentrate.MS346.1(M+1)。

Under 0 ℃, triethylamine (24 μ L, 0.174mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (30mg, 0.087mmol) and 4-chloroformate nitrophenyl ester (18mg, the 0.091mmol) solution in tetrahydrofuran (THF) (1mL).After 1 hour, add 1H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone (21mg, 0.096mmol), triethylamine (48 μ L, 0.348mmol) and methylene dichloride (1mL), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 88% methylene chloride/methanol], obtain title compound (9.5mg).MS?589.2369(M+1)。

Embodiment 121

-9-yl }-2,4-dioxo-1,3,8-thriazaspiro [4.5] decane-8-methane amide

-9-amine

-9-yl }-2,4-dioxo-1,3,8-thriazaspiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (12 μ L, 0.087mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (30mg, 0.087mmol) and 4-chloroformate nitrophenyl ester (18mg, the 0.091mmol) solution in tetrahydrofuran (THF) (1mL).After 1 hour, add 1,3,8-thriazaspiro [4.5] decane-2,4-diones (15mg, 0.091mmol), triethylamine (48 μ L, 0.348mmol) and DMF (1mL), and with this mixture heating up to 40 ℃.After 18 hours, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying [100% methylene dichloride → 88% methylene chloride/methanol], obtain title compound (12mg).MS?541.1955(M+1)。

Embodiment 122

-9-yl }-4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1,3-benzodiazepine

-3-yl) piperidines-1-methane amide

-9-amine

Trifluoroacetic acid (1mL) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In the solution of-9-aminocarbamic acid tert-butyl ester (110mg, 0.57mmol) in methylene dichloride (2mL).After 2 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is washed with saturated brine, through dried over mgso, filter and concentrate.MS346.1(M+1)。

-9-yl }-4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1,3-benzodiazepine

-3-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (7.0 μ L, 0.05mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (17mg, 0.05mmol) and 4-chloroformate nitrophenyl ester (10.0mg, the 0.05mmol) solution in tetrahydrofuran (THF) (3mL).After 20 minutes, add 3-piperidin-4-yl-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine -2-keto hydrochloride (14mg, 0.05mmol) and triethylamine (21 μ L, 0.15mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).Organic layer washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (22mg).MS?617.2609(M+1)。

Basic preparation method according to embodiment 122, the embodiment compound in the preparation table 14.

Table 14

Embodiment 127

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-4-(2-oxo-1,2-dihydro-quinoline-3-yl) piperidines-1-methane amide

-9-amine

Trifluoroacetic acid (1mL) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (110mg, 0.57mmol) in methylene dichloride (2mL).After 2 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is washed with saturated brine, through dried over mgso, filter and concentrate.MS346.1(M+1)。

-9-yl }-4-(2-oxo-1,2-dihydro-quinoline-3-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (5.0 μ L, 0.035mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (12.0mg, 0.035mmol) and 4-chloroformate nitrophenyl ester (7.0mg, the 0.035mmol) solution in tetrahydrofuran (THF) (3mL).After 20 minutes, add 3-piperidin-4-yl quinoline-2 (1H)-ketone (8.0mg, 0.035mmol) and triethylamine (15 μ L, 0.11mmol), and this mixture is warming to room temperature.After 1 hour, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).Organic layer washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (17mg).MS?600.2340(M+1)。

Basic preparation method according to embodiment 127, the embodiment compound in the preparation table 15.

Table 15

Embodiment 132

-9-yl }-4-(3-oxo-2,3-dihydro-pyridazine-4-yl) piperidines-1-methane amide

-9-amine

Hydrochloric acid (4.0M diox liquid; 1.0mL, 4.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-aminocarbamic acid the tert-butyl ester is (in 36mg, 0.081mmol) De diox (1mL) solution.After 18 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.1(M+1)。

-9-yl }-4-(3-oxo-2,3-dihydro-pyridazine-4-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (37 μ L, 0.50mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (70mg, 0.167mmol) and 4-chloroformate nitrophenyl ester (34mg, the 0.167mmol) solution in tetrahydrofuran (THF) (1mL).After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (49 μ L, 0.67mmol) of 4-piperidin-4-yl pyridazine-3 (2H)-ketone (30mg, 0.167mmol), and this mixture is warming to room temperature.After 4 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction (3x).Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (51mg).MS?551.2152(M+1)。

Basic preparation method according to embodiment 132, the embodiment compound in the preparation table 16.

Table 16

Embodiment 137

-9-yl }-1-oxo-2,8-diaza spiro [4.5] decane-8-methane amide

-9-amine

-9-yl }-1-oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (32.2 μ L, 0.23mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (32mg, 0.077mmol) and 4-chloroformate nitrophenyl ester (15mg, the 0.077mmol) solution in tetrahydrofuran (THF) (1mL).After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (43 μ L, 0.31mmol) of 2,8-diaza spiro [4.5] decane-1-ketone (15mg, 0.077mmol), and this mixture is warming to room temperature.After 72 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction (3x).Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 87% methylene chloride/methanol), obtain title compound (13mg).MS?526.2204(M+1)。

Basic preparation method according to embodiment 137, the embodiment compound in the preparation table 17.

Table 17

Embodiment 140

-9-yl }-4-(6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

-9-amine

Under 0 ℃, triethylamine (33.0 μ L, 0.24mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In-9-amine hydrochlorate (33.0mg, 0.079mmol) and 4-chloroformate nitrophenyl ester (16.0mg, the 0.079mmol) solution in tetrahydrofuran (THF) (1mL).After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (22 μ L, 0.16mmol) of 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (15.0mg, 0.079mmol), and this mixture is warming to room temperature.After 4 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction (3x).Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (22mg).MS?565.2306(M+1)。

Basic preparation method according to embodiment 140, the embodiment compound in the preparation table 18.

Table 18

Embodiment 144

-9-yl }-1,3-dioxo-2,8-diaza spiro [4.5] decane-8-methane amide

-9-amine

Hydrochloric acid (4.0M diox liquid; 1.0mL, 4.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-aminocarbamic acid the tert-butyl ester is (in 36mg, 0.081mmol) De diox (1mL) solution.After 18 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.1(M+1)。

-9-yl }-1,3-dioxo-2,8-diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (0.28mL, 1.97mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (275mg, 0.66mmol) and 4-chloroformate nitrophenyl ester (139mg, the 0.69mmol) solution in tetrahydrofuran (THF) (2.5mL).After 15 minutes, add 2,8-diaza spiro [4.5] decane-1, the acetate of 3-diketone (WO 2004/076455) (180mg, 0.79mmol) methylene dichloride (2.5mL) solution and triethylamine (0.28mL, 1.97mmol), and this mixture is warming to room temperature.After 2 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction (3x).Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (213mg).MS540.2005(M+1)。

Basic preparation method according to embodiment 144, the embodiment compound in the preparation table 19.

Table 19

Embodiment 147

-9-yl }-1-methyl-2,4-dioxo-1,3,8-thriazaspiro [4.5] decane-8-methane amide

-9-amine

Trifluoroacetic acid (1mL, 13.5mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] in methylene dichloride (2mL) solution of t-butyl carbamate (120mg, 0.27mmol).After 1 hour, the concentrated and adding saturated sodium bicarbonate aqueous solution of this mixture.This mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over mgso, filter and concentrate.MS?346.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-1-methyl-2,4-dioxo-1,3,8-thriazaspiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (70 μ L, 0.50mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In-9-amine hydrochlorate (70mg, 0.167mmol) and 4-chloroformate nitrophenyl ester (34mg, the 0.167mmol) solution in tetrahydrofuran (THF) (2mL).After 15 minutes, add the 1-methyl isophthalic acid, the methylene dichloride of 3,8-thriazaspiro [4.5] decane-2,4-diones (31mg, 0.167mmol) (2mL) solution and triethylamine (93 μ L, 0.67mmol), and this mixture is warming to room temperature.After 4 hours, add saturated aqueous sodium carbonate, with this mixture ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (33mg).MS?555.2107(M+1)。

Embodiment 148

-9-yl }-3-methyl-2-oxo-2,3-dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-methane amide

-9-amine

Trifluoroacetic acid (1mL, 13.5mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In the solution of-9-aminocarbamic acid tert-butyl ester (120mg, 0.27mmol) in methylene dichloride (2mL).After 1 hour, add saturated sodium bicarbonate aqueous solution.This mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over sodium sulfate, filter and concentrate.MS?346.1(M+1)。

Under 0 ℃, triethylamine (30 μ L, 0.22mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine hydrochlorate (30mg, 0.07mmol) and 4-chloroformate nitrophenyl ester (14mg, 0.07mmol) are in tetrahydrofuran (THF) (1mL) solution.After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (40 μ L, 0.29mmol) of 3-methyl isophthalic acid H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone (17mg, 0.07mmol), and this mixture is warming to room temperature.After 72 hours, add saturated aqueous sodium carbonate, and with this mixture ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (10.9mg).MS?603.2451(M+1)。

Embodiment 149

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-4-(3-oxo-6-phenyl-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

-9-amine

Trifluoroacetic acid (1mL, 13.5mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in methylene dichloride (2mL) solution of t-butyl carbamate (120mg, 0.27mmol).After 1 hour, the concentrated and adding saturated sodium bicarbonate aqueous solution of this mixture.This mixture washs the organic extract liquid that merges with dichloromethane extraction (3x) with saturated brine, through dried over mgso, filter and concentrate.MS?346.1(M+1)。

-9-yl }-4-(3-oxo-6-phenyl-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (33 μ L, 0.24mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (33mg, 0.08mmol) and 4-chloroformate nitrophenyl ester (16mg, the 0.08mmol) solution in tetrahydrofuran (THF) (1mL).After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (22 μ L, 0.16mmol) of 6-phenyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (20mg, 0.08mmol), and this mixture is warming to room temperature.After 2 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (22mg).MS?627.2498(M+1)。

Embodiment 150 and embodiment 151

4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl)-N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl } piperidines-1-methane amide and N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-4-(3-oxo-6-propyl group-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

-9-amine

Step B:4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl)-N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (34 μ L, 0.24mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (36mg, 0.081mmol) and 4-chloroformate nitrophenyl ester (16mg, the 0.081mmol) solution in methylene dichloride (1mL).After 15 minutes, add 6-cyclopropyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone and 4-piperidin-4-yl-6-propyl group pyridazine-3 (2H)-alcohol/ketone mixtures (18mg, 0.081mmol) methylene dichloride (1mL) solution and triethylamine (11 μ L, 0.08mmol), and this mixture is warming to room temperature.After 3 hours, add saturated aqueous sodium carbonate, this mixture ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain 4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl)-N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] piperidines-1-methane amide (11mg); MS 591.2507 (M+1) and N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl]-4-(3-oxo-6-propyl group-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide (14mg); MS 593.2689 (M+1).

Embodiment 152

-9-yl }-4-(2-oxo-1,2-dihydropyridine-4-yl) piperidines-1-methane amide

-9-amine

-9-yl }-4-(2-oxo-1,2-dihydropyridine-4-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (40 μ L, 0.285mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (33mg, 0.095mmol) and 4-chloroformate nitrophenyl ester (19mg, the 0.095mmol) solution in methylene dichloride (2mL).After 15 minutes, add methylene dichloride (1mL) solution and the triethylamine (26 μ L, 0.19mmol) of 3-piperidin-4-yl pyridine-2 (1H)-keto hydrochloride (23mg, 0.105mmol), and this mixture is warming to room temperature.After 3 hours, add saturated aqueous sodium carbonate, with this mixture extraction ethyl acetate.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (8.5mg).MS?650.2244(M+1)。

Embodiment 153

-9-yl }-8,10-dioxo-3,9-diaza spiro [5.5] hendecane-3-methane amide

-9-amine

-9-yl }-8,10-dioxo-3,9-diaza spiro [5.5] hendecane-3-methane amide

Under 0 ℃, triethylamine (30.3 μ L, 0.215mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (30mg, 0.072mmol) and 4-chloroformate nitrophenyl ester (15mg, the 0.075mmol) solution in tetrahydrofuran (THF) (0.5mL).After 15 minutes, add 3,9-diaza spiro [5.5] hendecane-2, methylene dichloride (1mL) solution of the acetate (19mg, 0.079mmol) of 4-diketone and triethylamine (30.3 μ L, 0.215mmol), and this mixture is warming to room temperature.After 2 hours, add saturated aqueous sodium carbonate, and with this mixture ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (17.4mg).MS?554.2196(M+1)。

Embodiment 154

-9-yl }-4-oxo-1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-8-methane amide

-9-amine

Hydrochloric acid (4.0M diox liquid; 4mL, 16.0rnmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate is (in 27mg, 0.061mmol) De diox (4mL) solution.After 18 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.2(M+1)。

Under 0 ℃, triethylamine (42 μ L, 0.30mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (25mg, 0.061mmol) and 4-chloroformate nitrophenyl ester (14mg, the 0.070mmol) solution in tetrahydrofuran (THF) (5mL).After 40 minutes, add 1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-4-keto hydrochloride (21mg, 0.091mmol), triethylamine (34 μ L, 0.24mmol) and chloroform (5mL), and this mixture is warming to room temperature.After 18 hours, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic extract liquid washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 85% methylene chloride/methanol), obtain title compound (22mg).MS?525.2000(M+1)。

Embodiment 155

N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Substantially the method preparation of summarizing according to Preparation Example 10 compounds.MS590.2326(M+1)。

Embodiment 156

N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-ethyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Substantially the method preparation of summarizing according to Preparation Example 10 compounds.MS536.2557(M+1)。

Embodiment 157

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-the 1-methane amide

Substantially the method preparation of summarizing according to Preparation Example 47 compounds.MS575.2227(M+1)。

Embodiment 158

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] oxazine]-1-methane amide

Steps A: (6S, 9R)-6-(2,6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

Sulfuric acid (0.15mL, 2.85mmol) is added to [(6S, 9R)-6-(2,6-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in methyl alcohol (1.5mL) solution of t-butyl carbamate (120mg, 0.285mmol).This reaction mixture is heated to 60 ℃.After 3 hours, with reactant saturated sodium bicarbonate aqueous solution termination reaction.Mixture,, filters and concentrates through dried over mgso with the saturated brine washing with dichloromethane extraction (3x).MS?336.2(M+1)。

Step B:N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (38 μ L, 0.27mmol) is added to (6S, 9R)-6-(2,6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine (95mg, 0.28mmol) and 4-chloroformate nitrophenyl ester (60mg, the 0.30mmol) solution in tetrahydrofuran (THF) (4mL).After 15 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (68mg, 0.31mmol) and triethylamine (120 μ L, 0.85mmol), and this mixture is warming to room temperature.After 16 hours, add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic extract liquid washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 93% methylene chloride/methanol), obtain title compound (128mg).MS?581.2702(M+1)。

Substantially the method for summarizing according to Preparation Example 158, the embodiment compound in the preparation table 20.

Table 20

Embodiment 162

N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] oxazine]-1-methane amide

Steps A: 2-{1-[(6S, 9R)-and 9-amino-6-(2,6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-the 1-methyl ethoxy } ethanol

Methylsulfonic acid (78 μ L, 1.19mmol) is added to [(6S, 9R)-6-(2,6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] in ethylene glycol (4mL) solution of t-butyl carbamate (104mg, 0.24mmol).This reaction mixture is heated to 60 ℃.After 18 hours, make this mixture cool to room temperature, add saturated sodium bicarbonate aqueous solution.This mixture dichloromethane extraction (3x).The organic extract liquid saturated sodium bicarbonate aqueous solution, the saturated brine washing through dried over mgso, is filtered and is concentrated, and obtains title compound.MS?366.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] oxazine]-1-methane amide

Under 0 ℃, triethylamine (53 μ L, 0.38mmol) is added to 2-{1-[(6S, 9R)-9-amino-6-(2,6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-3-yl]-the 1-methyl ethoxy } in ethanol (63mg, 0.17mmol) and the solution of 4-chloroformate nitrophenyl ester (38mg, 0.19mmol) in tetrahydrofuran (THF) (10mL).After 20 minutes, adding 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (60mg, 0.26mmol), triethylamine (96.4 μ L, 0.67mmol) and chloroform (10mL), and with this mixture heating up to 40 ℃.After 16 hours, make the reaction mixture cool to room temperature.Add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction (3x).The organic extract liquid saturated sodium bicarbonate aqueous solution, the saturated brine washing through dried over mgso, is filtered and is concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 91% methylene chloride/methanol), obtain title compound (64mg).MS?625.2989(M+1)。

Embodiment 163

-9-yl }-2-oxo-2,3-dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-method preparation that methane amide is summarized according to Preparation Example 120 substantially.MS?589.2314(M+1)。

Embodiment 164

-9-yl }-4-(6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide steps A: (6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 5.0mL, 20.0mmol) be added to [(6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate is (in 265mg, 0.60mmol) De diox (5mL) solution.After 18 hours, this reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?346.1(M+1)。

Under 0 ℃, triethylamine (22 μ L, 0.16mmol) is added to (6S, 9R)-6-(2,6-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (15mg, 0.04mmol) and 4-chloroformate nitrophenyl ester (19mg, the 0.043mmol) solution in tetrahydrofuran (THF) (5mL).After 30 minutes, add 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (15mg, 0.08mmol), triethylamine (22 μ L, 0.16mmol) and chloroform (5mL), and with this mixture heating up to 50 ℃.After 30 minutes, make the reaction mixture cool to room temperature.Add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (15mg).MS?565.2346(M+1)。

Embodiment 165

N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Steps A: (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 3.0mL, 12.0mmol) be added to [(6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] t-butyl carbamate is (in 40mg, 0.085mmol) De diox (3mL) solution.After 2 hours, this reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?372.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 0 ℃, triethylamine (55 μ L, 0.39mmol) is added to (6S, 9R)-6-(2,6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In-9-amine hydrochlorate (40mg, 0.10mmol) and 4-chloroformate nitrophenyl ester (22mg, the 0.11mmol) solution in tetrahydrofuran (THF) (5mL).After 30 minutes, add 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (38mg, 0.20mmol), triethylamine (55 μ L, 0.39mmol) and chloroform (5mL), and with this mixture heating up to 50 ℃.After 30 minutes, make the reaction mixture cool to room temperature.Add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic extract liquid washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over mgso, filters also concentrated.Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride/methanol), obtain title compound (15mg).MS?591.2536(M+1)。

Embodiment 166

N-{ (6S, 9R)-6-(2-fluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl }-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Substantially the method preparation of summarizing according to Preparation Example 10 compounds.MS572.2377(M+1)。

Embodiment 167

N-{ (6S, 9R)-6-cyclohexyl-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Substantially the method preparation of summarizing according to Preparation Example 10 compounds.MS560.2974(M+1)。

Embodiment 168

N-{ (6S, 9R)-6-(2,3-dichlorophenyl)-3-ethyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Substantially the method preparation of summarizing according to Preparation Example 62 compounds.MS569.1784(M+1)。

Embodiment 169

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Steps A: [(3R, 6S)-2-cyano group-6-(2,3-difluorophenyl) azepine

-3-yl] t-butyl carbamate

Under-20 ℃, with [(3R, 6S)-6-(2, the 3-difluorophenyl)-and 2-oxa-azepan-3-yl] t-butyl carbamate (0.67g, 1.97mmol) tetrahydrofuran (THF) (10mL) solution slowly be added to the greening hydrogenation zirconocene (zirconocene chloride hydride) (0.76g, 2.95mmol) tetrahydrofuran (THF) (5.0mL) solution in.After 15 minutes, this mixture is warming to room temperature.After 3 hours, add trimethyl silane formonitrile HCN (1.31mL, 9.84mmol).After 16 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges Rochelle ' s salt solution (the 1.0M aqueous solution), the salt water washing through dried over sodium sulfate, is filtered also concentrated.MS?352.1(M+1)。

Step B:[(3R, 6S)-1-ethanoyl-2-cyano group-6-(2,3-difluorophenyl) nitrogen heterocyclic Heptane-3-yl] t-butyl carbamate

Under 0 ℃, triethylamine (1.29mL, 9.25mmol) is added to [(3R, 65)-2-cyano group-6-(2, the 3-difluorophenyl) azepan-3-yl] in methylene dichloride (20mL) solution of t-butyl carbamate (0.65g, 1.85mmol).Add diacetyl oxide (0.53mL, 5.55mmol) and this mixture is warming to room temperature.After 16 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying (99% dichloromethane/ethyl acetate → 70% dichloromethane/ethyl acetate), obtain title compound (144mg).MS?394.1(M+1)。

Step C:(3R, 6S)-1-ethanoyl-2-(amino methyl)-6-(2,3-difluorophenyl) nitrogen Heterocycle heptane-3-yl] t-butyl carbamate

With Raney nickel (2800, the soup compound of water; With washing with alcohol (2x); 0.5g) be added in ethanol (10mL) solution of [(3R, 6S)-1-ethanoyl-2-cyano group-6-(2,3-difluorophenyl) azepan-3-yl] t-butyl carbamate (80.0mg, 0.20mmol).Pass into ammonia 3 minutes in the reaction mixture and this mixture is stirred under the 40psi nitrogen atmosphere.After 4 hours, reaction mixture is filtered and concentrates.MS?398.2(M+1)。

Step D:[(6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-5,6,7,8,9,9a-six hydrogen-1H-imidazo [1,5-a] azepine

-9-yl] t-butyl carbamate

With in acetic acid (3mL) solution of [(3R, 6S)-1-ethanoyl-2-(amino methyl)-6-(2,3-difluorophenyl) azepan-3-yl] t-butyl carbamate (22mg, 0.055mmol) and be heated to 80 ℃.After 6 hours, make the reaction mixture cool to room temperature.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.MS?380.1(M+1)。

Step e: [(6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine

-9-yl] t-butyl carbamate

Magnesium oxide (IV) (46.0mg, 0.53mmol) is added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-5,6,7,8,9,9a-six hydrogen-1H-imidazo [1,5-a] azepine -9-yl] in toluene (7mL) solution of t-butyl carbamate (20.0mg, 0.053mmol).Reaction mixture is heated to backflow.After 8 hours, add other magnesium oxide (IV) (46.0mg, 0.53mmol).After 16 hours, make the reaction mixture cool to room temperature.This mixture is filtered, with methanol wash and concentrated.Through preparation of lamina chromatogram purification (9% ethanol/methylene), obtain title compound (5mg).MS?378.1(M+1)。

Step F: (6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 3.0mL, 12.0mmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine

The 9-yl] in methylene dichloride (3mL) solution of t-butyl carbamate (33mg, 0.087mmol).After 2 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS278.1(M+1)。

Step G:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-the 1-methane amide under 0 ℃, triethylamine (66 μ L, 0.476mmol) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-and 3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine

In-9-amine hydrochlorate (30.0mg, 0.108mmol) and 4-chloroformate nitrophenyl ester (31.0mg, the 0.152mmol) solution in tetrahydrofuran (THF) (10mL).After 20 minutes, the adding spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (hydrochloride (95mg, 0.325mmol) of 1 ' H)-ketone, triethylamine (66 μ L, 0.476mmol) and trichloromethane (10mL).Reaction mixture is heated to 40 ℃.After 16 hours, make this mixture cool to room temperature and concentrated.Add saturated aqueous sodium carbonate, and with this mixture dichloromethane extraction.Organic layer washs with saturated sodium bicarbonate aqueous solution (3x), saturated brine, through dried over sodium sulfate, filters also concentrated.Through reversed-phase HPLC purifying (C-18,95% water/acetonitrile → 5% water/acetonitrile wherein contain 0.1% trifluoroacetic acid), obtain title compound (3.55mg).MS?523.2274(M+1)。

Embodiment 170

Substantially according to the described method preparation of Preparation Example 169 compounds.MS581.2660(M+1)。

Embodiment 171

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R; 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6; 7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone

Steps A: (3S, 6S)-3-allyl group-6-(2,3-difluorophenyl) azepan-2- Ketone and (3R, 6R)-3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one

With Lawesson ' s reagent [2,4-two (4-p-methoxy-phenyl)-1,3-dithio-2,4-two phosphetane-2,4-disulphide] (0.97g, 2.39mmol) be added to (3S, 6S)-3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) in the suspension of azacycloheptan-2-one (634mg, 2.39mmol) in toluene (50mL).After 18 hours, that reaction mixture is concentrated in cooling bath.Through silica gel chromatography purifying (100% hexane → 70% hexane/ethyl acetate), obtain title compound (372mg).MS?282.1(M+1)。

Step B:1-{[(2Z, 3S, 6S)-3-allyl group-6-(2,3-difluorophenyl) nitrogen heterocyclic heptan Alkane-2-subunit] amino }-4,4, the pure and mild 1-{[(2Z of 4-trifluoro fourth-2-, 3R, 6R)-3-alkene Propyl group-6-(2,3-difluorophenyl) azepan-2-subunit] amino }-4,4, the 4-trifluoro Fourth-2-alcohol

Under 60 ℃, mercury chloride (II) (96mg, 0.36mmol) is added to (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one (100mg, 0.36mmol), 1-amino-4,4, the hydrochloride (167mg of 4-trifluoro fourth-2-alcohol, 0.93mmol) and the solution of triethylamine (150 μ L, 1.07mmol) in ethanol (2mL) in.After 5 minutes, make the reactant cool to room temperature.This mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound.MS?391.1(M+1)。

Step C:(6S, 9S)-9-allyl group-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

(6R, 9R)-9-allyl group-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Dichromic acid pyridine (296mg, 0.79mmol) is added to 1-{[(2Z, 3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-subunit] amino }-4,4, the pure and mild 1-{[(2Z of 4-trifluoro fourth-2-, 3R, 6R)-and 3-allyl group-6-(2,3-difluorophenyl) azepan-2-subunit] amino }-4,4, in 4-trifluoro fourth-2-alcohol (123g, 0.32mmol) solution in acetonitrile (10mL).After 48 hours, add other dichromic acid pyridine (296mg, 0.79mmol).After 18 hours, this mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol).Through reversed-phase HPLC repurity (95% water/acetonitrile → 5% water/acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (51mg).MS?371.1(M+1)。

Step D:[(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid and (6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid

Sodium periodate (265mg, 1.24mmol) and potassium permanganate (22mg, 0.14mmol) are added to (6S, 9S)-9-allyl group-6-(2, the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

(6R, 9R)-9-allyl group-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine In (51mg, 0.14mmol) solution in tetrahydrofuran (THF) (3mL) and water (5mL).After 16 hours, add the saturated sodium sulfite aqueous solution and methylene dichloride, and transfer to pH 4 with this pH value of solution of hydrochloric acid.Mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains the hydrochloride of title compound.MS389.0(M+1)。

Step e: 1-{[(6S, 9S)-and 6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R; 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6; 7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone

With triethylamine (70 μ L, 0.50mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (33mg, 0.17mmol) and 1-hydroxyl-7-azepine benzotriazole (20mg, 0.144mmol) be added to [(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid hydrochloride and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid hydrochloride (61mg, 0.144mmol), and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (in the solution of 1 ' H)-ketone (38mg, 0.17mmol) in methylene dichloride (5mL).After 18 hours, reaction mixture is heated to 45 ℃.1.5 after hour, that this mixture is concentrated.Through reversed-phase HPLC purifying (95% water/acetonitrile → 5% water/acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (34mg) of racemic mixture form.MS?590.2207(M+1)。

Embodiment 172

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R; 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7; 8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Step B:1-{[(2Z, 3S, 6S)-3-allyl group-6-(2,3-difluorophenyl) nitrogen heterocyclic heptan Alkane-2-subunit] amino }-3-methoxyl group-pure and mild 1-of 3-methyl fourth-2- { [(2Z, 3R, 6R)-3-allyl group-6-(2,3-difluorophenyl) azepan-2-subunit] Amino }-3-methoxyl group-3-methyl fourth-2-alcohol

Under 60 ℃, with mercury chloride (II) (96mg, 0.36mmol) be added to (3S, 6S)-3-allyl group-6-(2,3-difluorophenyl) azacycloheptan-2-one and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azacycloheptan-2-one (100mg, 0.36mmol), in 1-amino-3-methoxyl group-3-methyl fourth-2-alcohol (174mg, 1.31mmol) solution in ethanol (2mL).After 30 minutes, make the reactant cool to room temperature.This mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains title compound.MS381.2(M+1)。

Step C:(6S, 9S)-9-allyl group-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

(6R, 9R)-9-allyl group-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

With dichromic acid pyridine (383mg, 1.02mmol) be added to 1-{[(2Z, 3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-subunit] amino }-3-methoxyl group-pure and mild 1-{[(2Z of 3-methyl fourth-2-, 3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-subunit] amino-3-methoxyl group-3-methyl fourth-2-alcohol (155g, 0.41mmol) solution in acetonitrile (15mL) in.After 48 hours, add other dichromic acid pyridine (383mg, 1.02mmol).After 18 hours, this mixture is filtered and concentrates.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride/methanol), obtain title compound (23mg).MS?361.2(M+1)。

Step D:[(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine -9-yl] acetic acid and (6R, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid

Sodium periodate (123mg, 0.57mmol) and potassium permanganate (10mg, 0.064mmol) are added to (6S, 9S)-9-allyl group-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

In (23mg, 0.064mmol) solution in tetrahydrofuran (THF) (3mL) and water (3mL).After 16 hours, add other potassium permanganate (10mg, 0.064mmol) and water (2ml).After 2 hours, add the saturated sodium sulfite aqueous solution and methylene dichloride, and transfer to pH 4 with this pH value of solution of hydrochloric acid.Mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through dried over mgso, obtains the hydrochloride of title compound.MS?389.0(M+1)。

Step e: 1-{[(6S, 9S)-and 6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

Under 45 ℃, with triethylamine (31 μ L, 0.22mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (14mg, 0.075mmol) and 1-hydroxyl-7-azepine benzotriazole (9.0mg, 0.063mmol) be added to [(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid hydrochloride and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine

-9-yl] acetic acid hydrochloride (26mg, 0.063mmol), and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (in the solution of 1 ' H)-ketone (16mg, 0.075mmol) in methylene dichloride (3mL).1.5 after hour, that this mixture is concentrated.Through reversed-phase HPLC purifying (95% water/acetonitrile → 5% water/acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (34mg) of racemic mixture form.MS?580.2704(M+1)。

Embodiment 173

N-[(6S, 9S)-3-cyclopropyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

Steps A: N-[(3R, 6S)-6-(2,3-difluorophenyl)-2-hydrazono-azepan- The 3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) Piperidines-1-methane amide

With a hydrazine hydrate (1.46mL, 30.1mmol) be added to N-[(3R, 65)-6-(2, the 3-difluorophenyl)-2-sulphur oxa-azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) in methyl alcohol (20mL) solution of piperidines-1-methane amide (502mg, 1.00mmol).After 30 minutes, that reactant is concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates, and obtains title compound (515mg).MS?499.1(M+1)。

Step B:N-[(6S, 9S)-3-cyclopropyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

With triethylamine (20 μ L, 0.142mmol) be added to N-[(3R, 6S)-6-(2, the 3-difluorophenyl)-2-hydrazono-azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide (59mg, 0.118mmol) and cyclopropanecarbonyl chloride (11 μ L, 0.124mmol) methylene dichloride (1mL) solution in, and with this mixture heating up to 45 ℃.After 20 hours, that reactant is concentrated.Add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/(10% ammonium hydroxide/methyl alcohol)], obtain title compound (57mg).MS549.2524(M+1)。

Substantially according to the described method of Preparation Example 173 compounds, the embodiment compound in the preparation table 21.

Table 21

Embodiment 180

N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 10mL, 40.1mmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] in Isosorbide-5-Nitrae-dioxs (5mL) solution of t-butyl carbamate (618mg, 1.384mmol).After 1 hour, reactant is concentrated, obtain the title compound (584mg) of dihydrochloride form.MS?347.1(M+1)。

Step B:N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (58 μ L, 0.417mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

In the tetrahydrofuran (THF) of-9-amine dihydrochloride (50mg, 0.119mmol) and 4-chloroformate nitrophenyl ester (25mg, 125mmol) (4mL) solution.After 15 minutes, add 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-dichloride (52mg, 0.179mmol), triethylamine (58 μ L, 0.417mmol) and methylene dichloride (3mL), this mixture is warming to room temperature.After 5 hours, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (38mg).MS?591.2223(M+1)。

Embodiment 181

N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl]-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-amine

The tertiary butyl in the solution that trifluoroacetic acid (7.5mL, 101.3mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl] and-6,7,839-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine

-9-yl } carbamate (0.38g, 0.80mmol) is at methylene dichloride (15mL).After 1 hour, reaction mixture termination reaction saturated sodium bicarbonate aqueous solution and mixture dichloromethane extraction (3x).The organic extract liquid that merges, filters and the concentrated title compound that obtains through dried over mgso with the washing saturated brine.MS?373.1(M+1)。

Step B:N-[(6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

Under 0 ℃, with 1,1 '-carbonyl dimidazoles (24.0mg, 0.15mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

In the tetrahydrofuran (THF) of-9-amine (28mg, 0.075mmol) (1.0mL) solution.After 30 minutes, add other 1,1 '-carbonyl dimidazoles (11.0mg, 0.068mmol).After 30 minutes, add 3-methyl isophthalic acid-piperidin-4-yl-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones (26mg, 0.113mmol), and with this mixture heating up to 60 ℃.After 1 hour, add other 3-methyl isophthalic acid-piperidin-4-yl-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones (23mg, 0.099mmol).After 1 hour, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (33mg).MS?631.2566(M+1)。

Embodiment 182

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-amine

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (42 μ L, 0.298mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-amine dihydrochloride (50mg, 0.119mmol) and 1,1 '-solution of carbonyl dimidazoles (29mg, 0.179mmol) in tetrahydrofuran (THF) (2mL) in.After 1 hour, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (33mg, 0.149mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.2.5 after hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (37mg).MS?592.2087(M+1)。

Substantially according to the described method of Preparation Example 182 compounds, the embodiment compound in the preparation table 22.

Table 22

Embodiment 185

-9-yl]-1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Steps A: N-[(6S, 9R)-and 6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (13 μ L, 0.092mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-amine (32mg, 0.092mmol) and 1,1 '-solution of carbonyl dimidazoles (29mg, 0.179mmol) in tetrahydrofuran (THF) (1mL) in.After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (26mg, 0.111mmol) and methylene dichloride (1mL), and with this mixture heating up to 60 ℃.After 1 hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (28mg).MS?606.2231(M+1)。

Embodiment 186

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Steps A: N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (39 μ L, 0.281mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-amine dihydrochloride (50rag, 0.112mmol) and 1,1 '-solution of carbonyl dimidazoles (32mg, 0.197mmol) in tetrahydrofuran (THF) (1mL) in.After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (31mg, 0.135mmol) and methylene dichloride (1mL), and with this mixture heating up to 60 ℃.After 3 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (64mg).MS?632.2384(M+1)。

Embodiment 187

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl }-1 '-(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-methane amide

Steps A: N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (26 μ L, 0.185mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (31mg, 0.074mmol) and 1,1 of-9-amine '-tetrahydrofuran (THF) (1mL) solution of carbonyl dimidazoles (21mg, 0.129mmol) in.After 1 hour, add 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (23mg, 0.089mmol) and methylene dichloride (1mL), and with this mixture heating up to 60 ℃.2.5 after hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (42mg).MS?636.2330(M+1)。

Embodiment 188

Under 0 ℃, triethylamine (39 μ L, 0.281mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-amine dihydrochloride (50rag, 0.112mmol) and 1,1 '-solution of carbonyl dimidazoles (32mg, 0.197mmol) in tetrahydrofuran (THF) (1mL) in.After 1 hour, add 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone (35mg, 0.135mmol) and methylene dichloride (1mL), and with this mixture heating up to 60 ℃.2.5 after hour, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges is dry through S-WAT, filters and concentrates.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (64mg).MS?662.2487(M+1)。

Embodiment 189

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] piperidines]-the 1-methane amide

Under 0 ℃, triethylamine (52 μ L, 0.370mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (62mg, 0.148mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (48mg, 0.296mmol) in tetrahydrofuran (THF) (5mL) in.After 30 minutes, add 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (51mg, 0.185mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.1.5 after hour, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (33mg).MS576.2143(M+1)。

Embodiment 190

-9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrole [2,3-b] pyridine slightly also]-the 1-methane amide

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-amine

With hydrochloric acid (4.0M diox liquid; 10mL, 40.1mmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] in Isosorbide-5-Nitrae-dioxs (5mL) solution of t-butyl carbamate (440mg, 0.93mmol).1.5 after hour, reactant is concentrated, obtains the title compound (425mg) of dihydrochloride form.MS?347.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Under 0 ℃, triethylamine (39 μ L, 0.28mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (50mg, 0.112mmol) and 1,1 of-9-amine '-tetrahydrofuran (THF) (1.5mL) solution of carbonyl dimidazoles (32mg, 0.197mmol) in.After 30 minutes, add other 1,1 '-carbonyl dimidazoles (10mg, 0.062mmol).After 15 minutes, adding 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (37mg, 0.135mmol), triethylamine (39 μ L, 0.28mmol) and methylene dichloride (1.5mL), and with this mixture heating up to 60 ℃.1.5 after hour, make reaction mixture cool to room temperature and concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (38mg).MS?602.2306(M+1)。

Embodiment 191

-9-yl }-4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-methane amide

Steps A: (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-amine

-9-yl }-4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (42 μ L, 0.298mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (50mg, 0.119mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (44mg, 0.271mmol) in tetrahydrofuran (THF) (4mL) in.After 1 hour, add 1-piperidin-4-yl imidazolidine-2,4-dione (27mg, 0.149mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.After 2 hours, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,90% water/acetonitrile → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (28mg).MS?556.2126(M+1)。

Embodiment 192

-9-yl }-4-(2-oxo-1,2-dihydroquinoline-3-yl) piperidines-1-methane amide

-9-yl }-4-(2-oxo-1,2-dihydroquinoline-3-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (50 μ L, 0.358mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (60mg, 0.143mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (41mg, 0.25mmol) in tetrahydrofuran (THF) (3mL) in.After 25 minutes, add 3-piperidin-4-yl quinoline-2 (1H)-ketone (33mg, 0.143mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.After 16 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).Organic layer washs with saturated brine, through dried over mgso, filters and concentrates.Through silica gel chromatography purifying [100% methylene dichloride → 95% methylene dichloride/(10% ammonium hydroxide/methyl alcohol)].Through reversed-phase HPLC repurity (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (57.5mg).MS?601.2312(M+1)。

Substantially according to the described method of Preparation Example 192 compounds, the embodiment compound in the preparation table 23.

Table 23

Embodiment 196

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl }-4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1,3-benzodiazepine

-3-yl) piperidines-1-methane amide

-9-yl }-4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1,3-benzodiazepine

-3-yl) piperidines-1-methane amide

The dihydrochloride (60mg, 0.143mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (41mg, 0.25mmol) in tetrahydrofuran (THF) (3mL) in.After 25 minutes, add 3-piperidin-4-yl-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine

The hydrochloride (40mg, 0.143mmol) of-2-ketone and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.After 16 hours, make reaction mixture cool to room temperature and concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (53mg).MS?618.2572(M+1)。

Substantially according to the described method of Preparation Example 196 compounds, the embodiment compound in the preparation table 24.

Table 24

Embodiment 200

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl }-4-(3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

-9-amine

-9-yl }-4-(3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Under 0 ℃, triethylamine (16 μ L, 0.112mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine The dihydrochloride (20mg, 0.045mmol) and 1,1 of-9-amine '-tetrahydrofuran (THF) (1.0mL) solution of carbonyl dimidazoles (13mg, 0.079mmol) in.After 20 minutes, add other 1,1 '-carbonyl dimidazoles (7.3mg, 0.045mmol).After 30 minutes, add again 4-piperidin-4-yl pyridazine-3 (2H)-ketone (10mg, 0.056mmol) and methylene dichloride (1.0mL), and with this mixture heating up to 60 ℃.After 16 hours, make reactant cool to room temperature and concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (20mg).MS?578.2315(M+1)。

Substantially according to the described method of Preparation Example 200 compounds, the embodiment compound in the preparation table 25.

Table 25

Embodiment 203

-9-amine

The dihydrochloride (50mg, 0.119mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (34mg, 0.209mmol) in tetrahydrofuran (THF) (2mL) in.After 15 minutes, add other 1,1 '-carbonyl dimidazoles (10mg, 0.062mmol).After 30 minutes, add again 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (28mg, 0.143mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.After 1 hour, make reaction mixture cool to room temperature and concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (54mg).MS?566.2313(M+1)。

Substantially according to the described method of Preparation Example 203 compounds, the embodiment compound in the preparation table 26.

Table 26

Embodiment 206

-9-yl }-4-(2-oxo-Isosorbide-5-Nitrae-dihydroquinazoline-3 (2H)-yl) piperidines-1-methane amide

-9-amine

Under 0 ℃, triethylamine (50 μ L, 0.356mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (60mg, 0.143mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (41mg, 0.25mmol) in tetrahydrofuran (THF) (3mL) in.After 25 minutes, add 3-piperidin-4-yl-3, the hydrochloride (38mg, 0.143mmol) of 4-dihydroquinazoline-2 (1H)-ketone and methylene dichloride (3mL), third with this mixture heating up to 60 ℃.After 16 hours, make reaction mixture cool to room temperature and concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (54mg).MS?604.2404(M+1)。

Embodiment 207

-9-yl }-1-oxo-2,8-dichloro spiral shell [4.5] decane-8-methane amide of mixing

-9-amine

With hydrochloric acid (4.0M diox liquid; 5mL, 20.0mmol) be added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl } in Isosorbide-5-Nitrae-dioxs (5mL) solution of t-butyl carbamate (440mg, 0.93mmol).1.5 after hour, reaction mixture is concentrated, the dihydrochloride of the title compound that obtains (425mg).MS?347.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl }-1-oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (16 μ L, 0.112mmol) is added to (6S, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

The dihydrochloride (20mg, 0.045mmol) and 1,1 of-9-amine '-solution of carbonyl dimidazoles (13mg, 0.079mmol) in tetrahydrofuran (THF) (1.0mL) in.After 20 minutes, add other 1,1 '-carbonyl dimidazoles (7.3mg, 0.045mmol).After 30 minutes, add again hydrochloride (11mg, 0.056mmol) and the methylene dichloride (1.0mL) of 2,8-diaza spiro [4.5] decane-1-ketone, and with this mixture heating up to 60 ℃.After 16 hours, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (14mg).MS?553.2315(M+1)。

Embodiment 208

N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl }-1-oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Steps A: 2-[(6S, 9R)-and 9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-3-yl] propan-2-ol

With hydrochloric acid (4.0M diox liquid; 5mL, 20.0mmol) be added to [(6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] in Isosorbide-5-Nitrae-dioxs (5mL) solution of t-butyl carbamate (176mg, 0.417mmol).After 1 hour, reaction mixture is concentrated, the dihydrochloride of the title compound that obtains (175mg).MS?323.1(M+1)。

Step B:N-{ (6S, 9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl }-1-oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, triethylamine (18 μ L, 0.126mmol) is added to 2-[(6S, 9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -3-yl] propan-2-ol dihydrochloride (20mg, 0.051mmol) and 1,1 '-solution of carbonyl dimidazoles (14mg, 0.09mmol) in tetrahydrofuran (THF) (1.0mL) in.After 10 minutes, add other 1,1 '-carbonyl dimidazoles (8.0mg, 0.05mmol).After 30 minutes, add 2,8-diaza spiro [4.5] silicon-1-keto hydrochloride (12mg, 0.06mmol) and methylene dichloride (1.0mL), and with this mixture heating up to 60 ℃.After 16 hours, that reactant is concentrated.Through reversed-phase HPLC purifying (C-18,10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (20mg).MS?503.2570(M+1)。

Embodiment 209

1-(1-{[6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones

With triethylamine (146 μ L, 1.044mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (69mg, 0.358mmol) and 1-hydroxyl-7-azepine benzotriazole (41mg, 0.298mmol) be added to [6-(2,3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride (127mg of acetic acid, 0.298mmol) and 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-dichloride (87mg, 0.298mmol) in the solution in acetonitrile (3mL) and DMF (1mL).After 4 hours, reaction mixture is diluted with ethyl acetate and saturated sodium bicarbonate aqueous solution.This mixture ethyl acetate extraction with the saturated brine washing, through dried over sodium sulfate, filters and the concentrated title compound that obtains.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile, wherein contain 0.1% trifluoroacetic acid) obtain racemic trans-compound 1-(1-{[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones and 1-(1-{[(6R, 9S)-6-(2,3-difluorophenyl)-3-(2; 2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones; MS590.2299 (M+1), and racemic cis-compound 1-(1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] ethanoyl } piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-d] pyridin-2-ones and 1-(1-{[(6R, 9R)-6-(2,3-difluorophenyl)-3-(2; 2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones; MS 590.2293 (M+1).(2 * 35cm), 60% hexane (0.1% diethylamine)/ethanol separates this trans enantiomer with 6mL/min speed through Chiralpak OD post.

Embodiment 210

1-{[6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9S)-6-(2,3-difluorophenyl)-3-(2; 2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone

With triethylamine (17 μ L, 0.123mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (8.0mg, 0.042mmol) and 1-hydroxyl-7-azepine benzotriazole (5.0mg, 0.035mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride of acetic acid and [(6R, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] acetic acid hydrochloride (15.0mg, 0.035mmol) and 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] in the solution of dichloride (13mg, 0.046mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (12mg) of racemic mixture form.MS?575.2197(M+1)。

Embodiment 211

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2,3-difluorophenyl)-3-(2; 2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone

With triethylamine (17 μ L, 0.123mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (8.0mg, 0.042mmol) and 1-hydroxyl-7-azepine benzotriazole (5.0mg, 0.035mmol) be added to [(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride of acetic acid and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] acetic acid hydrochloride (15.0mg, 0.035mmol) and 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] in the solution of dichloride (13mg, 0.046mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (12mg) of racemic mixture form.MS?575.2196(M+1)。

Embodiment 212

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2; the 3-difluorophenyl)-and 3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1; 2,4]-triazolo [4,3-a] azepine

With triethylamine (12 μ L, 0.084mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (6.0mg, 0.029mmol) and 1-hydroxyl-7-azepine benzotriazole (3.0mg, 0.024mmol) be added to [(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride of acetic acid and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] acetic acid hydrochloride (10.0mg, 0.024mmol) and 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] in the solution of dichloride (8mg, 0.029mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound of racemic mixture form

(9mg)。MS?565.2752(M+1)。

Embodiment 213

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2; the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1; 2,4]-triazolo [4,3-a] azepine

With triethylamine (21 μ L, 0.149rnmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (8.0mg, 0.040mmol) and 1-hydroxyl-7-azepine benzotriazole (5.0mg, 0.033mmol) be added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl } acetic acid hydrochloride and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } acetic acid hydrochloride (15.0mg, 0.033mmol) and 2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] in the solution of dichloride (11mg, 0.040mmol) in DMF (0.25mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (14mg) of racemic mixture form.MS?601.2370(M+1)。

Embodiment 214

1-{[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9S)-6-(2; the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] hydrochloride (15.0mg, 0.035mmol) of acetic acid and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-2 ' (in the solution of 1 ' H)-ketone (9mg, 0.042mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (18mg) of racemic mixture form.MS?591.2157(M+1)。

Embodiment 215

-9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2; the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] hydrochloride (15.0mg, 0.035mmol) of acetic acid and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-2 ' (in the solution of 1 ' H)-ketone (9mg, 0.042mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (17mg) of racemic mixture form.MS?591.2166(M+1)。

Embodiment 216

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R; 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

With triethylamine (41 μ L, 0.295mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (19.0mg, 0.101mmol) and 1-hydroxyl-7-azepine benzotriazole (11.0mg, 0.084mmol) be added to [(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride of acetic acid and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] hydrochloride (35.0mg of acetic acid, 0.084mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-2 ' (1 ' H)-ketone (22.0mg, 0.101mmol) in the solution in DMF (0.5mL) and acetonitrile (3mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (36mg) of racemic mixture form.MS?581.2698(M+1)。

Embodiment 217

1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-{[(6R; 9R)-and 6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8; 9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone

With triethylamine (43 μ L, 0.31mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (20.0mg, 0.106mmol) and 1-hydroxyl-7-azepine benzotriazole (12.0mg, 0.089mmol) be added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } acetic acid hydrochloride and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } hydrochloride (40.0mg, 0.089mmol) of acetic acid and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazines]-2 ' (in the solution of 1 ' H)-ketone (23.0mg, 0.106mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (46mg) of racemic mixture form.MS?617.2322(M+1)。

Embodiment 218

1-(2-{ (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone and 1-(2-{ (6R, 9R)-6-(2, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone

Steps A: (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl)-the acetic acid methyl ester and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl)-the acetic acid methyl ester

Under 0 ℃, TMS two azomethanes (0.22mL, 0.438nunol) are added to { (6S, 9S)-6-(2, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } acetic acid hydrochloride and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl } in the solution of hydrochloride (33mg, 0.073mmol) in methylene dichloride (3mL) and methyl alcohol (1mL) of acetic acid.After 30 minutes, that reaction mixture is concentrated.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain title compound (23mg).MS?430.1(M+1)。

Step B:{ (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl)-acetaldehyde and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl)-acetaldehyde

Under-78 ℃, with diisobutyl aluminum chloride (1.0M hexane liquid; 0.25mL, 0.252mmol) be added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } methyl acetate and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } in the solution of methyl acetate (18mg, 0.042mmol) in methylene dichloride (2mL).Add other two parts of diisobutyl aluminum chlorides (0.25mL, 0.252mmol).1.5 after hour, under-78 ℃, reaction mixture Rochelle ' s salt solution (3mL) termination reaction.Add ethyl acetate and make this mixture be warming to room temperature.This mixture, filters and the concentrated title compound that obtains through dried over sodium sulfate with the extraction ethyl acetate and with the saturated brine washing.MS?400.1(M+1)。

Step C:1-(2-{ (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

Sodium cyanoborohydride (7.0mg, 0.111mmol) is added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl } acetaldehyde and (6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine

-9-yl } acetaldehyde (22.0mg, 0.055mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (in the solution of 1 ' H)-ketone (12.0mg, 0.055mmol) in methyl alcohol (3mL).Reaction mixture transfers to pH 3 with acetic acid.After 20 minutes, that this mixture is concentrated.Through reversed-phase HPLC purifying (10% acetonitrile/water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (17mg) of racemic mixture form.MS?603.2528(M+1)。

Embodiment 219

4-(1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone

-9-yl] in the hydrochloride (15.0mg, 0.035mmol) and the solution of 4-piperidin-4-yl pyridazine-3 (2H)-ketone (8.0mg, 0.046mmol) in DMF (0.5mL) of acetic acid.After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (15mg) of racemic mixture form.MS?551.2190(M+1)。

Embodiment 220

4-(1-{[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone

-9-yl] hydrochloride of acetic acid and [(6R, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] in the hydrochloride (15.0mg, 0.035mmol) and the solution of 4-piperidin-4-yl pyridazine-3 (2H)-ketone (8.0mg, 0.046mmol) in DMF (0.5mL) of acetic acid.After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (16mg) of racemic mixture form.MS?551.2199(M+1)。

Embodiment 221

1-(1-{[6S, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2,4-dione and 1-(1-{[(6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2,4-dione

With triethylamine (17 μ L, 0.123mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (8.0mg, 0.042mmol) and 1-hydroxyl-7-azepine benzotriazole (5.0mg, 0.035mmol) be added to [(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] hydrochloride of acetic acid and [(6R, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] in the hydrochloride (15.0mg, 0.035mmol) and the solution of 1-piperidin-4-yl imidazolidine-2,4-dione (10mg, 0.056mmol) in DMF (0.5mL) of acetic acid.After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (16mg) of racemic mixture form.MS?555.2144(M+1)。

Embodiment 222

1-(1-{[(6S, 9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2,4-dione and 1-(1-{[(6R, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2,4-dione

-9-yl] hydrochloride of acetic acid and [(6R, 9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine -9-yl] in the hydrochloride (15.0mg, 0.035mmol) and the solution of 1-piperidin-4-yl imidazolidine-2,4-dione (10mg, 0.053mmol) in DMF (0.5mL) of acetic acid.After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (16mg) of racemic mixture form.MS?555.2161(M+1)。

Embodiment 223

3-[1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } piperidin-4-yl]-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine

-2-ketone and 3-[1-{[6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } piperidin-4-yl]-1,3,4,5-tetrahydrochysene-2H-1,3-benzodiazepine -2-ketone

With triethylamine (16 μ L, 0.116mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (8.0mg, 0.040mmol) and 1-hydroxyl-7-azepine benzotriazole (5.0mg, 0.033mmol) be added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl } acetic acid hydrochloride (15.0mg, 0.033mmol) and 4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1,3-benzodiazepine

-3-yl) in piperidines greening (11.0mg, 0.040mmol) solution in DMF (0.5mL).After 18 hours, trifluoroacetic acid (20 μ L) adds.Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (17mg) of racemic mixture form.MS643.2833(M+1)。

Embodiment 224

4-(1-{[(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone

With triethylamine (3.0 μ L, 0.024mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (5.0mg, 0.024mmol) and 1-hydroxyl-7-azepine benzotriazole (3.0mg, 0.024mmol) be added to [(6S, 9S)-6-(2,3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl] in acetic acid hydrochloride (10.0mg, 0.024mmol) and the 6-methyl-solution of 4-piperidin-4-yl pyridazine-3 (2H)-ketone (6.0mg, 0.029mmol) in DMF (0.5mL).After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (6mg) of racemic mixture form.MS?555.2909(M+1)。

Embodiment 225

4-(1-{[6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine

-9-yl] ethanoyl } piperidin-4-yl)-6-methyl pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6; 7,8,9-tetrahydrochysene-5H-[1; 2,4]-triazolo [4,3-a] azepine -9-yl] ethanoyl } piperidin-4-yl)-6-methyl pyridazine-3 (2H)-ketone

With triethylamine (43.0 μ L, 0.31mmol), N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (20.0mg, 0.106mmol) and 1-hydroxyl-7-azepine benzotriazole (12.0mg, 0.089mmol) be added to (6S, 9S)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine

-9-yl } in the hydrochloride (40.0mg, 0.089mmol) and the 6-methyl-solution of 4-piperidin-4-yl pyridazine-3 (2H)-ketone (21.0mg, 0.106mmol) in DMF (0.5mL) of acetic acid.After 18 hours, add trifluoroacetic acid (20 μ L).Through reversed-phase HPLC purifying (100% water → 100% acetonitrile wherein contains 0.1% trifluoroacetic acid), obtain the title compound (45mg) of racemic mixture form.MS?591.2520(M+1)。

The present invention adopts some specified scheme to be described and to illustrate, but this area professional and technical personnel should be clear, in the situation that does not depart from essence of the present invention and scope, can carry out various changes, variation, modification, replacement, omission or additional to the inventive method and scheme.For example, because Mammals is treated the reactions change of any indication to the compounds of this invention shown in using, can use effective dose, but not the given dose that above provides.Equally, whether the specific pharmacological reaction of observing also will or exist the type of pharmaceutical carriers, preparation and the administering mode of employing to change to some extent according to selected particular active compounds, should consider according to purpose of the present invention and practice variation and the difference of this class expected results.Therefore, scope of the present invention is limited by attached claim, and answers claim rationally broadly to explain.

Claims

1. formula I compound and pharmacologically acceptable salt thereof and diastereomer monomer:

Wherein:

Z is selected from:

A is CH ₂

B is CH ₂

D is independently selected from N and C (R ¹);

R ¹Be selected from:

1) H, C ₁-C ₆Alkyl, C _3-6Cycloalkyl and heterocycle, wherein said heterocycle represents stable 5-7 unit's monocycle or bicyclic heterocycle system of 8-11 unit, it is saturated or unsaturated, and be comprised of carbon atom and 1-4 heteroatoms that is selected from N, O and S, it is unsubstituted or is selected from independently of one another following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

D) heteroaryl, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: imidazoles, different

Azoles,

Azoles, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine and thiazole;

E) heterocycle, it is unsubstituted or is selected from independently of one another R by 1-5 ⁴Substituting group replace, and wherein heterocycle is selected from: azetidine, two

Alkane, dioxolane, morpholine, trimethylene oxide, piperazine, piperidines, tetramethyleneimine, tetrahydrofuran (THF) and tetrahydropyrans;

F) (F) _pC _1-3Alkyl,

G) halogen,

h)OR ⁴，

i)O(CH ₂) _sOR ⁴，

j)CO ₂R ⁴，

k)CN，

l)NR ¹⁰R ¹¹，

m)O(CO)R ⁴；

2) aryl or heteroaryl are selected from: phenyl, imidazoles, different

Azoles, Azoles, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine and thiazole, it is unsubstituted or is selected from independently of one another following substituting group and replaces by one or more:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

C) (F) _pC _1-3Alkyl,

D) halogen,

e)OR ⁴，

f)CO ₂R ⁴，

g)(CO)NR ¹⁰R ¹¹，

h)SO ₂NR ¹⁰R ¹¹，

i)N(R ¹⁰)SO ₂R ¹¹，

j)S(O) _mR ⁴，

k)CN，

L) NR ¹⁰R ¹¹, and

m)O(CO)R ⁴；

R ²Be selected from the phenyl that is replaced by halogen, or C _3-6Cycloalkyl;

R ⁴Be H;

W is-NH-or-CH ₂-;

X is C;

Y is O;

P is 0 to 2q+1, for the substituting group with q carbon atom;

M is 0,1 or 2;

S is 1,2 or 3;

R ¹⁰And R ¹¹Be independently selected from: H, C _1-6Alkyl, (F) _pC _1-6Alkyl, C _3-6Cycloalkyl, aryl, heteroaryl and benzyl, it is unsubstituted or by halogen, hydroxyl or C ₁-C ₆Alkoxyl group replaces, R ¹⁰And R ¹¹Randomly form together and be selected from following ring: azetidinyl, pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described ring are unsubstituted or are selected from independently of one another R by 1-5 ⁴Substituting group replace; Wherein said aryl refers to be at most the carbocyclic ring of any stable monocycle of 7 yuan of rings, and wherein said ring is aromatic ring; Wherein said heteroaryl represents the stable 5-7 unit's monocycle that comprises an aromatic ring or condensed-bicyclic heterocycle system of 9-10 unit, and it is comprised of carbon atom and 1-4 heteroatoms that is selected from N, O and S.

2. the formula I compound and pharmacologically acceptable salt and the steric isomer monomer that have formula Ie:

Wherein:

A is CH ₂

R ¹, R ², R ⁴, W and Z as defined in claim 1.

3. the formula I compound and pharmacologically acceptable salt and the steric isomer monomer that have formula If:

Wherein:

A is CH ₂

R ¹, R ², R ⁴, W and Z as defined in claim 1.

4. a compound and pharmacologically acceptable salt and diastereomer monomer, it is selected from:

5. a compound and pharmacologically acceptable salt and diastereomer monomer, it is selected from:

6. pharmaceutical composition, it comprises the compound of inert support and claim 1.

7. the compound of claim 1 is in the purposes of preparation in the medicine, and described medicine is used for the CGRP receptor active of antagonism Mammals.

8. the compound of claim 1 is in the purposes of preparation in the medicine, and described medicine is used for the treatment of, controls, improves or alleviates headache in the mammalian subject that these needs are arranged, migraine or neural the headache or its danger partially.

9. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of serotonin agonist, pain killer, antiphlogiston, antihypertensive drug and anticonvulsive drug, and described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

10. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of antianxiety agent and psychosis, and described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

11. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of beta-Blocking agent and calcium channel blocker, described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

12. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of thymoleptic, selective serotonin reuptake inhibitor and NE reuptake inhibitor, described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

13. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of botulinum toxin type A and botulinum toxin type B, described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

14. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from following medicine: the vanillin receptor antagonist, adenosine 1 antagonist, the NR2B antagonist, the Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 antagonist, the granzyme B inhibitor, endothelin antagonist, the norepinephrine precursor, nitric oxide synthase inhibitor activity, psychosis, brad ykinin antagonists, the gap connects inhibitor, the AMPA/KA antagonist, the sigma-receptor agonist, the chloride channel toughener, oxidase inhibitor, opiates agonist and the LTRA purposes in the preparation medicine, described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

15. the compound or pharmaceutically acceptable salt thereof of claim 1 and the second are selected from the purposes of medicine in the preparation medicine of antiemetic, prokinetic agent and histamine H 1 antagonist, described medicine is used for the treatment of or prevention of migraine, partially neural headache and headache.

16. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of serotonin agonist, pain killer, antiphlogiston and anticonvulsive drug.

17. pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of angiotensin-ii antagonist, angiotensin I antagonist, angiotensin-convertion enzyme inhibitor and renin inhibitor.

18. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of antianxiety agent and psychosis.

19. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of beta-Blocking agent and calcium channel blocker.

20. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of thymoleptic, selective serotonin reuptake inhibitor and NE reuptake inhibitor.

21. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of botulinum toxin type A or botulinum toxin type B.

22. pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from following medicine: the vanillin receptor antagonist, adenosine 1 antagonist, the NR2B antagonist, the Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 antagonist, the granzyme B inhibitor, endothelin antagonist, the norepinephrine precursor, nitric oxide synthase inhibitor activity, psychosis, brad ykinin antagonists, the gap connects inhibitor, the AMPA/KA antagonist, the sigma-receptor agonist, the chloride channel toughener, oxidase inhibitor, opiates agonist and LTRA.

23. a pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity, and the second for the treatment of significant quantity is selected from the medicine of antiemetic, prokinetic agent and histamine H 1 antagonist.