CN101090902A

CN101090902A - Cgrp receptor antagonists

Info

Publication number: CN101090902A
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 and Co Inc
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2004-10-13
Filing date: 2005-10-12
Publication date: 2007-12-19
Anticipated expiration: 2025-10-12
Also published as: CN101090902B; 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 the rat and the mankind, CGRP is respectively to differ one and three amino acid whose α-and β-formal representation.CGRP-α and CGRP-β demonstrate similar biological.When being released from cell, CGRP causes its biologically by combining with specific cell surface receptor, and this combination mainly is and activatory adenylate cyclase (adenylyl cyclase) coupling.People have discerned 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, as the pathological process of migraine and neural partially 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).Main artery 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).The meninx artery diameter increased during the dural electricity irritation of rat made, this effect can block by using CGRP (8-37)-a kind of peptide class CGRP antagonist in advance (Williamson etc., Cephalalgia, 1997,17,525-531).In the rat hormesis of gasserian ganglion is quickened 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 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 the effect of blood vessel by the CGRP antagonist.

According to the show, neurone (the Williamson etc. of the vasorelaxation action sensitization trigeminal nerve caudatum (caudalis) of meningeal arteries in the rat 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 to be used for humans and animals, particularly the useful medicine of people's the disease that relates to CGRP.This class disease comprises migraine and neural partially 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., the 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 neural partially 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 the agent of a kind of migraine treatment safely and effectively (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 of treatment.

Summary of the invention

The present invention relates to as the CGRP receptor antagonist and be used for the treatment of or prevent the CGRP diseases associated, 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:

With

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 R independently of one another by 1-5 ⁴Substituting group replace,

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

E) heterocycle, it is unsubstituted or is selected from R independently of one another 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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

Wherein any two R independently ¹Can randomly 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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

Wherein be positioned at any two R independently on same atom or the adjacent atom ²Can randomly form together and be selected from following ring: cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, _ azoles base, _ azoles quinoline base, 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 or morpholinyl, described ring are unsubstituted or are selected from R independently of one another 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 ¹¹And

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 R independently of one another 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 ¹¹And

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 ¹¹And

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 ¹¹And

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 ¹¹And

m)O(CO)R ⁴，

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 R independently of one another 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 ¹¹And

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:

Or

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

Or

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

Or

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

Or

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

Or

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

Or

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

Or

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

Or

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 R independently of one another 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.

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 R independently of one another by 1-5 ⁴Substituting group replace,

D) heteroaryl, it is unsubstituted or is selected from R independently of one another 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 R independently of one another 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 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)N，

L) NR ¹⁰R ¹¹And

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 R independently of one another by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, different _ azoles, _ azoles, 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, different _ the azoles quinoline, different _ azoles alkane, morpholine, _ the azoles quinoline, _ azoles alkane, 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 ¹¹And

M) O (CO) R ⁴And

2) aryl or heteroaryl, they are selected from: phenyl, benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, different _ azoles, _ azoles, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, thiazole, thiophene and triazole, 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 ¹¹And

m)O(CO)R ⁴，

Wherein be positioned at any two R independently on same atom or the adjacent atom ²Can randomly form together and be selected from following ring: cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, _ azoles base, _ azoles quinoline base, 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 ¹¹Can randomly form together and be selected from following ring: azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl, these rings are unsubstituted or are selected from R independently of one another 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 ¹¹And

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 the following formula structure thus:

Or

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 the following formula structure thus:

Or

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:

Or

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 the following formula structure thus:

Or

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

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

Or

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:

Or

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

Or

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

Or

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:

Or

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

Or

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:

Or

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:

Or

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

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 the structure of one of following formula thus:

R ³Be independently selected from H, replacement or unsubstituted C ₁-C ₃Alkyl, F, CN and CO ₂R ⁴R ^7aAnd R ^7bBe selected from R independently of one another 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 the mixture and the purified or partially purified compound thereof 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 desired, can will measure after their reagent derivation with the asymmetric center that comprises known absolute configuration.

If desired, 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, adopts standard method then, 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 added.The racemic mixture of The compounds of this invention also can directly separate by utilizing chiral stationary phase to pass through chromatographic process, and this method is well known in the art.

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

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 is meant not have two keys or triple-linked straight chain, side chain and ring texture.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 is meant that each ring is at most the stable monocycle or the bicyclic carbocyclic ring of 7 yuan of rings, and wherein at least one ring is an 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 " heterocyclic " expression are stable or bicyclic heterocycle system of 8-11 unit, it can be saturated or unsaturated, and form by carbon atom and 1-4 heteroatoms that is selected from N, O and S, and wherein the heteroatoms of nitrogen and sulphur can be randomly oxidized, nitrogen heteroatom can be randomly by quaternized, and comprise wherein any heterocycle as defined above and phenyl ring condensed dicyclo.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 azetidine, chroman, dihydrofuran, dihydropyrane, two _ alkane, dioxolane, six hydrogen azepines _, imidazolidine, imidazolidone, tetrahydroglyoxaline, imidazolone, indoline, heterochromatic full, isoindoline, isothiazoline, isothiazolidine, different _ the azoles quinoline, different _ azoles alkane, morpholine, morpholone mai, _ azoles quinoline, _ azoles alkane, _ oxazolidone, trimethylene oxide, 2-oxo six hydrogen azepines _, 2-oxa-piperazine, 2-oxa-piperidines, 2-oxa-tetramethyleneimine, piperazine, piperidines, pyrans, pyrazolidine, pyrazoline, tetramethyleneimine, pyrroline, the quinine pyridine, tetrahydrofuran (THF), tetrahydropyrans, parathiazan, thiazoline, thiazolidine, parathiazan and N-oxide compound thereof.

Unless otherwise indicated, 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, as pyridyl, and it is made up of carbon atom and 1-4 heteroatoms that is selected from N, O and S, and wherein the heteroatoms of nitrogen and sulphur can be randomly oxidized, and nitrogen heteroatom can be randomly by quaternized, and comprise wherein any heterocycle as defined above and phenyl ring condensed dicyclo.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, benzisoxa _ azoles, cumarone, benzothiazole, thiophene, benzotriazole, benzo _ azoles, carboline, cinnolines, furans, furazan, imidazoles, indazole, indoles, indolizine, isoquinoline 99.9, isothiazole, different _ azoles, naphthyridines, _ diazole, _ azoles, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, quinazoline, quinoline, quinoxaline, tetrazolium, thiadiazoles, thiazole, thiophene, triazine, triazole and N-oxide compound thereof.

As C ₁-C ₆Term in the alkoxyl group " alkoxyl group " is meant 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 " is meant, 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 is meant 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, as the mineral acid or the organic acid salt of amine; Acidic-group is as the alkali salt of carboxylic acid or organic salt etc.Pharmacologically acceptable salt comprises, for example, and the conventional non-toxic salt or the quaternary ammonium salt of the parent compound that forms 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, as acetate, 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, 2-acetoxy-benzoic acid, 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, is defined as a plurality of annular atoms N-C (R sometimes ⁶) ₂, C=C (R ⁶) or the like.

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 acetate, 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.

Use embodiment and compound disclosed herein to illustrate the present invention.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 as the method for the mammiferous CGRP acceptor of this antagonism of need, this method comprises the The compounds of this invention of using significant quantity.The present invention relates to the purposes of compound disclosed herein as the CGRP receptor antagonist.Method of the present invention is removed and can be treated outside the primate, particularly people, can also treat multiple other Mammalss.

Another embodiment of the invention relates to a kind of treatment, control, improve or alleviate the patient with the receptor related disease of CGRP or the method for illness, this 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 " is meant 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.Term used herein " treatment " is meant treatment or the mentioned illness of prophylactic treatment, 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 by mixing any composition that The compounds of this invention and pharmaceutically acceptable carrier are worth." pharmaceutically acceptable " is meant 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 being meant the prodrug that the individuality of this treatment of need is provided 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: ¹²⁵Acceptor combines that (Edvinsson etc., (2001) Eur.J.Pharmacol.415 39-44) carries out according to the method for describing substantially in I-CGRP and the SK-N-MC cytolemma.Put it briefly, (25 μ g) comprising 10 pM with film ¹²⁵1ml binding buffer liquid [10mM HEPES, pH7.4, the 5mM MgCl 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 after 3 hours in the room temperature insulation by filtering.With screen plate with ice-cold mensuration damping fluid washing three times after, at air drying.Add scintillation solution (50 μ l) and go up the counting 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) determines Ki.

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 ₂Following growth.Measure for carrying out cAMP, before mensuration with cell with 5 * 10 ⁵The culture plate (Becton-Dickinson) of the density of individual cells/well is tiled in 96 holes poly--D-Methionin bag quilt is gone up and was cultivated about 18 hours.With cell with phosphate buffered saline (PBS) (PBS, σ) wash after, 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 again, cell carries out cAMP mensuration with the PBS washing and according to the scheme of manufacturer recommendation.Be defined as maximal stimulation on the basis with 100nM CGRP.Use Prism to generate dose-response curve.Calculate dosage-ratio (DR) and draw full Schild figure (Arunlakshana﹠amp with it; Schild (1959) Br.J.Pharmacol.14,48-58).

Recombinant receptor: with CRLR (Genbank add numbering [0237] L76380) as 5 ' NheI and 3 ' Pmel segment subclone in expression vector pIREShyg2 (BD Biosciences Clontech).With people RAMP1 (Genbank add numbering AJ001014) as 5 ' NheI and 3 ' NotI segment subclone in expression vector pIRESpuro2 (BD Biosciences Clontech).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 the 0.25% trypsin treatment pair cell that contains 0.1%EDTA to carry 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 common transfection CRLR of equivalent and RAMP1 makes up.After the transfection 24 hours, diluting cells and at second day bringing Selection In property 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 of express recombinant people 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 with the laboratory homogenizer and in 48, centrifugation after birth under the 000g.To precipitate resuspending in the capture buffer liquid that is added with 250mM sucrose and-70 ℃ of storages.Measure for carrying out combination, 10 μ g after births are being contained 10pM ¹²⁵1ml binding buffer liquid (10mMHEPES, pH7.4, the 5mM MgCl 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.(10mM HEPES, pH7.4) washing is three times with ice-cold mensuration damping fluid for filtrate.The adding scintillation solution is also counted culture plate on Topcount (Packard).Measure non-specific binding and by utilizing nonlinear least square to make bonded CPM data fitting in the binding constants (K that establishes an equation definite down _i) carry out data analysis:

Wherein Y is observed in conjunction with CPM, Y _MaxIn being in conjunction with number, Y _MinBe non-specific in conjunction with number, (Y _Max-Y _Min) be specificity in conjunction with number, %I _MaxBe maximum percent inhibition, %I _MinBe minimum percent inhibition, K _dIt is 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 culture plate (Corning) of the poly-D-Methionin bag quilt in 96 holes with the density of 85,000 cells/well and cultivated about 19 hours.Cell with PBS washing back and inhibitor contain L-L-glutamic acid and 1g/LBSA do not contain serum/low PROTEIN C ellgro perfect medium (Cellgro Complete Serum-Free/Low-Protein medium) (Mediatech, Inc.) in cultivation 30 minutes under 37 ℃ and 95% humidity.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)/(l+ (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, their K usually in aforementioned mensuration _iOr IC ₅₀Value is less than about 50 μ M.This result shows the intrinsic activity of The compounds of this invention as the CGRP receptor antagonist.

The present invention can become it as the character of CGRP antagonist to be used for the human and animal, 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 following illness of inertia or disease or alleviate its dangerous beneficial functional: headache; Migraine; Neural partially 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 tolerance 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 treatment of antagonism CGRP acceptor or prevention.Wherein particularly importantly be used for the treatment of or prophylactic treatment headache, migraine and neural partially 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 with other drug and is used for preventing, treat, control, improve or alleviating aforementioned diseases, illness or indication or its danger.

The compounds of this invention can be united with one or more other drugs and is used for the treatment of, prevent, control, improve disease or indication or its danger that formula I compound or other drug have curative effect, 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 in proper order 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 that 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, for example 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, _ promazine, 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, 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, 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 P substance antagonist; Endothelin antagonist; The norepinephrine precursor; Anxiolytic medicament, 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 as fluoxetine, paroxetine, Sertraline, duloxetine, escitalopram or citalopram; Thymoleptic are as amitriptyline, nortriptyline, clomipramine, imipramine, Venlafaxine, P-3693A, protriptyline, Desipramine, Trimipramine or imipramine; Leukotriene antagonist is 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 that Ergotamine and dihydroergotamine, as ergotocine, ergotocine, methylergobasine, metergoline, dihydroergotoxine methanesulfonate, DHO180, dihydroergocristine, dihydroergo cryptine(DCS 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 as Phenelzine; Calcium channel blocker is as flunarizine, sulphur nitrogen _ ketone, amlodipine, felodipine, nisoldipine, Isrodipine, nimodipine, lomerizine, Verapamilum, nifedipine or prochlorperazine; Nerous sedative is as olanzapine, droperidol, prochlorperazine, chlorpromazine and Quetiapine; Anticonvulsive drug is 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 Type B Toxins, botulin.

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, as xylometazoline, suprarenin, naphazoline, fourth card azoles quinoline, propylhexedrine or left-handed Desoxyephedrine; Antitussive is as caramiphen, pentoxyverine or Dextromethorphane Hbr; Diuretic(s); Short motion 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 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, 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, 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 be used to prevent, treat, control, improve or alleviate The compounds of this invention at 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 in proper order 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 that comprising The compounds of this invention.Therefore pharmaceutical composition of the present invention comprises except that 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 (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 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 together.Except that 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 the solid carrier of active ingredient and liquid vehicle or trickle pulverizing, and perhaps two kinds of carriers together evenly and closely combination if desired, make product be shaped to required preparation then.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.Tablet comprise active ingredient and with it blended be suitable for preparing the nontoxic pharmaceutically acceptable perfume compound of tablet.These perfume compound can be, for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent are as starch, gelatin or gum arabic; And lubricant, 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 as Zerol or Stearic diglyceride.They also can pass through U.S. Pat 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, 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, as lime carbonate, calcium phosphate or kaolin blended; Perhaps be the soft gelatin capsule form, wherein active ingredient is and water or oil medium, as peanut oil, whiteruss or mixed with olive oil.

Aqueous suspension comprise active substance and with it blended be suitable for preparing the vehicle of aqueous suspension.This class vehicle is a suspending agent, as Xylo-Mucine, methylcellulose gum, HPMC, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, as Yelkin TTS, the perhaps condensation product of alkylene oxide and lipid acid, as polyoxyethylene stearic acid ester, the perhaps condensation product of oxyethane and long chain aliphatic alcohol, as 17 oxygen ethene hexadecanols (heptadecaethyleneoxycetanol), the perhaps condensation product of oxyethane and lipid acid and hexitol deutero-part ester, as octadecanoic acid ester of polyethylene glycol, the perhaps condensation product of oxyethane and lipid acid and hexitan (hexitol anhydrides) deutero-part ester is 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 the 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, 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 granule and comprising active ingredient and blended dispersion agent or wetting agent, suspending agent and one or more sanitass 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 as sweeting agent, perfume compound and tinting material.

Pharmaceutical composition of the present invention can also be an 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 by lipid acid and hexitan deutero-ester or part the 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 use those the above-mentioned suitable dispersion agents mentioned or wetting agent and suspending agent to prepare according to technology known in the art.Aseptic injection also can be nontoxic thinner or 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 fusion.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 by treatment patient's symptom adjustment.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, neural partially headache or the other diseases of treatment 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 disposable administration of per daily dose of about 0.1-100 milligram/kilogram the weight of animals or 2-6 administration of branch 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.Under 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, the given dose level and the administration frequency for any particular patient can change, it depends on multiple factor, comprises the severity 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 and by the ongoing treatment of curer.

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.As synthetic intermediate and final compound as described in the reaction scheme 1-17.

Reaction scheme

By the compound final compound of intermediate suc as formula I and formula II, and this paper has described the synthetic method of every kind of intermediate.

Generally, formula III can be connected by the urea shown in scheme 1 with the IV intermediate and carries out coupling.Intermediate 1The amine that obtains behind the deprotection can be converted into the reactive amino manthanoate, as the p-nitrophenyl carbamate 2, with its subsequently with 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 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, 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 the carbonyl dimidazoles cyclization subsequently, obtain the ring-type urea 28Deprotection disengages amine then 29

Scheme 5

Quinolone 34By negatively charged ion and the piperidone that obtains by 2-chloroquinoline and lithium diisopropylamine 31Prepared in reaction (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), handle 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 herein with another kind of dibromide alkylating reagent.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 38With suitable-1, the alkylation of 4-two chloro-2-butylene uses cesium carbonate to carry out in DMF, obtains spiral shell azepine oxindole 43(scheme 8).After under standard conditions, removing the SEM protecting group,, obtain two alcohol intermediates by the catalytic dihydroxy reaction of perosmic anhydride 45Decompose glycol with periodate oxidation, carry out then two key reduction aminations (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 benzo _ piperazine 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 52Under 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 a media with 2-amino-3-bromopyridine, use 2-(TMS) oxyethyl group methyl chloride to carry out alkylation of amide then, obtain product 55Crucial palladium be the volution of media 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 two step of key reductive deprotections, obtain spiral shell naphthyridines ketone (spiral shell naphthyridines) 57

Scheme 10

According to scheme 11 generalized ethylene linkage transposition strategies assembly hexanolactam again.Under the alkaline condition of gentleness, with 2,4-dimethoxybenzylamine hydrochloride is with 2, and the alkylation of 3-propylene bromide obtains 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 bromination things, for example use the catalytic arylation of palladium 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 primary amine hydrogenation of protection on the spot, obtain corresponding saturated lactan 65With 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, eliminate on the spot then 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 take place, obtain amino acid 70Closed loop under standard conditions is removed a tertbutyloxycarbonyl then, 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 at vinyl bromination thing 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).Closed loop under standard conditions is removed a tertbutyloxycarbonyl then, 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.Handle 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 the oxidation of dichromic acid pyridine, 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

Under some situation, final product can also further be modified for example substituent processing.These processing can include, but are not limited to the common known reduction of those skilled in the art, oxidation, alkylation, acidylate and hydrolysis reaction.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 more fully understanding the present invention.These embodiment only are illustrative, and should not be construed as is to limit the present invention by any way.

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) pyridine amino)

Under the room temperature, with sodium triacetoxy borohydride (14.5g, 68.7mmol) be added to 2,3 diamino pyridine (5.00g, 45.8mmol) and N-(tertbutyloxycarbonyl)-4-piperidone (9.58g is 48.1mmol) in the solution of (75mL) in ethylene dichloride.After 5 hours, add other sodium triacetoxy borohydride (1.8g) once more 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, solution is filtered 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＝13?Hz，2H)，3.46(m，1H)，2.98(brs，2H)，2.01(dd，J＝12，2?Hz，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, with carbonyl dimidazoles (0.70g 4.33mmol) is added to 2-amino-3-[(1-tertbutyloxycarbonyl piperidin-4-yl) amino] (1.15g is 3.93mmol) in the solution in acetonitrile (150mL) for pyridine.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(brs，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＝12?Hz，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, (1.03g 3.23mmol) is dissolved in the methyl alcohol (25 mL) and adds 2N salt acid ether (8mL) solution 3-dihydro-1H-imidazo [4,5-b] pyridine.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-dioxy-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1 -formyl chloride

Under 0 ℃, with phosgene (20%wt toluene solution; 1.8mL, 3.43mmol) being added to 2-oxo-1-piperidin-4-yl-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-dichloride _ (100mg, 0.343mmol) with 2, (0.50mL is in methylene dichloride 4.293mmol) (5mL) suspension for the 6-lutidine.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 solid title compound (48mg).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) pyrimidine amino)

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

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

Crude product 4-amino-5-[(1-tertbutyloxycarbonyl piperidin-4-yl that steps A is obtained) amino) (3.0g 18mmol) refluxed 2 days in tetrahydrofuran (THF) (250mL), and cooling also concentrates for pyrimidine and carbonyl dimidazoles.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, (1.2g, 3.7mmol) mixture in the two _ alkane (50mL) of 4N hydrogenchloride was room temperature vigorous stirring 3 hours for 9-dihydro-8H-purine-8-ketone.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

Toward 2-amino-5-fluorine pyridine of 0 ℃ (1.00g, 8.92mmol) and triethylamine (1.35g, 13.4mmol) add in the solution in methylene dichloride (30mL) trimethyl-acetyl chloride (1.29g, 10.7mmol) and DMAP (0.11g, 0.89mmol).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)-2,2-dimethyl propylene acid amides (1.34g, drip in tetrahydrofuran (THF) 6.83mmol) (25mL) solution tert-butyl lithium (1.31mL 1.7M solution, 20.5mmol).-78 ℃ through after 3 hours, (3.60g 10.2mmol) is added in the reactant and makes it be warming to room temperature with 4-dodecylbenzene sulfuryl azide.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 concentrate, resistates obtains title compound (0.275g) through twice order silica gel chromatography purifying (10% → 80%EtOAc/ hexane, 5% → 42%EtOAc/ hexane then) 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, (275mg 1.16mmol) is heated to 100 ℃ to 2-dimethyl propylene acid amides 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

(1.90g, hydrochloride 10.0mmol) are dissolved in tetrahydrofuran (THF) (100mL) and (Argonaut 11.5g) handles with the MP-carbonic ether with 3-azido--5-fluorine pyridine-2-amine.After 1 hour, this mixture is filtered, using more, the tetrahydrofuran (THF) of volume washes and concentrates.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, (2.95g 13.9mmol) is added to 5-fluorine pyridine-2 with sodium triacetoxy borohydride, the 3-diamines (1.18g, 9.28mmol), acetate (0.56g, 9.28mmol) and 1-(tertbutyloxycarbonyl)-4-piperidone (1.85g, 9.28mmol) 1, in the solution of 2-ethylene dichloride (20mL).After 1 hour, will react water (20mL) and stop and use dichloromethane extraction.Only after the dried over sodium sulfate, solution is filtered and evaporation, obtain crude product.Product is through chromatogram purification (silica gel, 5% → 15%MeOH/DCM; C-18 then, 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, with carbonyl dimidazoles (1.53g 9.41mmol) is added to 4-[(2-amino-5-fluorine pyridin-3-yl) amino] (0.73g is 2.35mmol) in the solution in acetonitrile (10mL) for piperidines-1-t-butyl formate.Reaction stirred exhausts (about 2 hours), vacuum evaporating solvent then until whole raw materials.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

(340mg 1.01mmol) is dissolved in methylene dichloride (5mL) and add trifluoroacetic acid (5mL) to 4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo [4,5-5] pyridine-1-yl) piperidines-1-t-butyl formate.After 2 hours, reactant is concentrated,, and at room temperature add 1 of 1N hydrochloric acid, 4-two _ alkane (2mL) solution with methylene dichloride (5mL) dilution.Concentrate and obtain title compound (302mg).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(500?MHz，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)3?1.73(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: hydrazono-9H-fluorenes-9-ylmethyl 4-[(tertbutyloxycarbonyl)] piperidines-1-first Acid esters

With 1-[(9H-fluorenes-9-yl) methoxycarbonyl]-the 4-piperidone (16.0g, 50.0mmol) and tert-butyl carbazate (7.25g, 55.5mmol) solution in ethanol (250mL) refluxed 1 hour.With solution cooling and concentrated.The title compound (21.0g) that adds ether (100mL) back generation white precipitate. 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(brs，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-] (10.0g, acetate 22.9mmol) (150mL) solution is with platinum oxide (1.0g) jolting 2 hours under 45psi hydrogen for piperidines-1-manthanoate.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] (20g 45.7mmol) is dissolved in trifluoroacetic acid (100mL) and stirring at room 1.5 hours to piperidines-1-manthanoate.Reactant is concentrated and resistates is dissolved in methyl alcohol, through the reversed-phase HPLC purifying.Separate purified 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(brs，6H)，3.05(brs，1H)，2.80(brs，2H)，1.89(brs，2H)，1.2(brs，2H)。

Step D:9H-fluorenes-9-ylmethyl 4-(5-oxo-3-phenyl-4, the 5-dihydro- 1H-1,2, the 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) (1.25mL refluxed 2 hours in tetrahydrofuran (THF) 7.1mmol) (30mL) solution containing diisopropyl ethyl amine.With reactant cooling and concentrated, heating for dissolving in acetonitrile then.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, the 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) piperidines-1-manthanoate (2.06g, 4.41mmol) and tetrahydrofuran (THF) (15mL) solution of diethylamine (15mL) stirring at room 2 hours.Reactant concentrates, 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, the 3-benzodiazepine _-2-ketone hydrochloric acid Salt

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

Under 0 ℃, with triphenylphosphine (39.2g, 0.150mol) and carbon tetrabromide (49.5g, 0.150mol) order is added to 2-(2-hydroxyethyl)-oil of mirbane (25.0g is in methylene dichloride 0.150mol) (400mL) solution.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 handled with ethyl acetate, and removes by filter sedimentary triphenylphosphine oxidation thing.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-

(22.8, (27.9g is in acetonitrile 0.121mol) (120mL) solution 0.351mol) to be added to 2-(2-bromotrifluoromethane)-oil of mirbane with the sodiumazide in the water (60mL).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 buttery title compound (22.8g).

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

With triphenylphosphine (31.1g, 0.118mol) and lime carbonate (50mg, (22.8g is in the solution of benzene 0.118mol) (500mL) 0.5mmol) to be added to 2-(2-azido-ethyl) oil of mirbane.To be reflected at stirring at room to abundant.Solvent removed in vacuo, resistates was handled 1 hour down at 100 ℃ with acetate (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, use ethyl acetate extraction then.Organic phase is with the saturated brine washing and through dried over sodium sulfate.Obtain buttery title compound (8.0g).MS?167(M+1)。

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

Add acetate, (8.00g, 48.1mmol) (9.59g, methyl alcohol 48.1mmol) (100mL) solution reaches pH5 with 1-tertbutyloxycarbonyl-4-piperidone to make 2-(2-amino-ethyl) oil of mirbane.(4.53g 72.2mmol) also will react stirring 3 hours to add sodium cyanoborohydride.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 buttery title compound (19.27g).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 } (17.2g is in dimethyl formamide 53.8mmol) (200mL) solution and stirring at room 2 hours for piperidines-1-t-butyl formate.Reactant extracts with saturated brine then 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 dark-coloured solid title compound (4.8g).

Step is (4-piperidyl)-1,3,4 G.3-, 5-tetrahydrochysene-2H-1, and the 3-benzodiazepine _- The 2-keto hydrochloride

Under 0 ℃, with 3-(1-tertbutyloxycarbonyl-4-piperidyl)-1,3,4,5-tetrahydrochysene-2H-1, the 3-benzodiazepine _-(4.80g, ethyl acetate 13.9mmol) (300mL) solution is saturated with hydrogenchloride for 2-ketone.The time reactant be warming to room temperature and stir and spend the night.Wash with solid filtering and with ethyl acetate.Ethyl acetate filtrate concentrating obtains second batch of product.Obtain solid title compound (2.94g).MS?246(M+1)。 ¹H?NMR(500MHz，CD ₃0D)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)3?3.05(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-fl-benzyl-4-hydroxy piperidine-4-yl)-the 2-chloroquinoline

Under-78 ℃ and argon atmospher, ((8.6mL is in tetrahydrofuran (THF) 61.1mmol) (140mL) solution 61.1mmol) to be added to diisopropyl ethyl amine for 1.6M, 38.2mL with the hexane solution of n-Butyl Lithium.After 1 hour, add 2-chloroquinoline (10.00g, tetrahydrofuran (THF) 61.1mol) (30mL) solution 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 the 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-

(11.0g 31.1mmol) refluxed 8 hours in 6N hydrochloric acid with 3-(1-benzyl-4-hydroxy piperidine-4-yl)-2-chloroquinoline.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-

(4.00g, methyl alcohol 12.6mmol) (500mL) solution argon-degassed adds 10% palladium charcoal (1.2g) with 3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) quinoline-2-(1H)-ketone.Reactant placed under the hydrogen-pressure and in 50 ℃ of heating 5.5 hours.With reactant cooling and filtration over celite.Concentrate and obtain title compound, 2.7g.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, the 4-diketone

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

With sodium cyanoborohydride (189mg, 3.01mmol) be added to the 1-boc-4-piperidone (500mg, 2.51mmol) and glycine ethyl ester hydrochloride (350mg is in methyl alcohol 2.51mmol) (12.5mL) solution.After 16 hours, make reaction terminating, concentrate and be assigned in methylene dichloride and the saturated sodium bicarbonate solution with saturated ammonium chloride 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] (100mg is in water 0.384mmol) (2mL) solution for piperidines-1-t-butyl formate.Add then that acetate transfers to 4-5 with reactant pH and with mixture in 40 ℃ of heating.After 16 hours,, obtain title compound (33mg) 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).

Step is piperidin-4-yl imidazolidine-2 C.1-, the 4-diketone

Trifluoroacetic acid (0.300mL) is added to 4-(2,4-dioxo alkyl imidazole-1-yl) piperidines-1-t-butyl formate, and (32mg is in methylene dichloride 0.113mmol) (1mL) solution.After 4 hours, reactant is concentrated, obtain title compound.MS184.04(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 (39.8g stirred 1 hour in DMF 0.337mol) (200mL) solution and with this mixture 0.404mol) to be added to the 7-azaindole through gradation in 25 minutes.Added 2-(TMS) oxyethyl group methyl chloride then lentamente (71.8mL 0.404mol), made the temperature of reaction mixture keep below 10 ℃ through 15 minutes.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

Through 30 minutes, with 1-{[2-(TMS) oxyethyl group] methyl }-1H-pyrrolo-[2,3-b] (43.1g, two _ alkane 0.174mol) (300mL) drips of solution is added to the pyridine hydrobromide perbromide, and (277g is in two _ alkane 0.868mol) (300mL) solution for pyridine.Use overhead mechanical stirrer with reactant in stirring at room.After 60 minutes, with biphase reaction mixture water (300mL) termination reaction 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), use salt solution (300mL) washing then, through MgSO ₄Drying is filtered and concentrating under reduced pressure.Crude product is dissolved in methylene dichloride immediately and solution is filtered the silica gel short column, with the methylene dichloride wash-out until garnet is eluted from post fully.Filtrate is used salt water washing (400mL) then 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] (65g is 0.154mol) in the solution of THF (880mL) and saturated aqueous ammonium chloride (220mL) for pyridin-2-ones.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), use salt water washing (100mL) then, 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]-(3.65g adds CF in methylene dichloride 8.60mmol) (80mL) solution to the 5-methyl-formiate 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) handles.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 ₂C1 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 add 1N sodium hydroxide (25.4mL, 25.4mmol).Reaction mixture 60 ℃ of heating 18 hours, is made it cooling then.This mixture is by adding 6N HCl acidifying, and filtering separation gained precipitation washes with water and vacuum-drying.Obtain near-white solid title compound.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-([the 2-TMS) oxyethyl group] methyl }-the 1H-pyrrolo-2,3-b] Pyridine

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 16.2g (39.8g 0.337mol) stirred 1 hour in the solution of DMF (200mL) and with this mixture 0.404mol) to be added to the 7-azaindole through gradation in 25 minutes.Slowly added 2-(TMS) oxyethyl group methyl chloride then (71.8mL 0.404mol), and made the temperature of reaction mixture keep below 10 ℃ through 15 minutes.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) two _ alkane (300mL) solution be added drop-wise to the pyridine hydrobromide perbromide through 30 minutes (277g be 0.868mol) in the suspension in two _ alkane (300mL).With overhead mechanical stirrer at the stirring at room reactant.After 60 minutes, with biphase reaction mixture water (300mL) termination reaction 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), use salt solution (300mL) washing then, through MgSO ₄Drying is filtered and concentrating under reduced pressure.Crude product is dissolved in methylene dichloride immediately and solution is filtered the silica gel short column, with the methylene dichloride wash-out until garnet is eluted from post fully.Filtrate is used salt water washing (400mL) then 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 '-pyrrolo-[2,3-b] pyridine-2 ' (1 ' H)-ketone

Toward suitable-1,4-two chloro-2-butylene (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 in the solution in DMF (175mL) cesium carbonate (10.7g, 32.9mmol).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), use salt water washing (100mL) then, 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 ' ((622mg 3.34mmol) adds perosmic anhydride (2-methyl-2-propanol solution of 25 μ L 2.5%) to 1 ' H)-ketone in the mixture of methylene dichloride (115mL).After 24 hours, 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 (and 640mg, 2.91mmol) at 3: 1 ethanol: add in the mixture in the water (160mL) sodium periodate (622mg, 2.91mmol).Treat that raw material consumption is intact, (50mL) adds reaction mixture lentamente with ammonium hydroxide.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), add tert-Butyl dicarbonate (635mg, 2.91mmol) after, add 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 '-(451mg 1.49mmol) is dissolved in ethyl acetate (3mL) and at room temperature add two _ alkane (7.5mmol) solution of 4N hydrochloric acid to dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-1-t-butyl formate.After 24 hours, vacuum is removed volatile matter and is obtained title compound (404 mg).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] _ piperazine]-2 ' (1 ' H)-ketone

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

(25.0g is 194.5mmol) with so two um hexamethyl two silazide (1.0M toward 2-amino-6-chloropyridine; 427.8mL, add tert-Butyl dicarbonate (46.69g, tetrahydrofuran (THF) 213.9mmol) (175mL) solution in tetrahydrofuran (THF) 427.8mmol) (175mL) solution.After 48 hours, reaction mixture is concentrated, 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 a spot of 60 ℃ 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] _ piperazine]-1-formic acid benzyl ester

With 10 minutes, (22.3mL added n-Butyl Lithium (2.5M in tetrahydrofuran (THF) 147.6mmol) (180mL) solution to past-20 ℃ N,N,N; 59.0mL, 147.6mmol).After 30 minutes, mixture is cooled to-78 ℃ and also adds (6-chloropyridine-2-yl) t-butyl carbamate (15.0g, tetrahydrofuran (THF) 65.6mmol) (60mL) solution with 15 fens clock times.2.5 after hour, with 10 minutes adding N-carbobenzoxy-(Cbz)-4-piperidone (23.0g, tetrahydrofuran (THF) 98.4mmol) (60mL) solution.Make reaction mixture be warming to room temperature.After 1 hour, reactant is heated to 40 ℃.After 18 hours, make the mixture termination reaction, mixture dichloromethane extraction (3x) with saturated sodium bicarbonate aqueous solution.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] _ piperazine]-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 '-pyrido [2,3-d] [1,3] _ piperazine]-(3.01g is in the solution of ethanol 7.76mmol) (150mL) for 1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 24 hours, add other palladium (10% palladium charcoal; 0.5g).After 4 hours,, obtain title compound (1.62g) with mixture filtration over celite and concentrated.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] _ piperazine]-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] _ piperazine]-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] _ piperazine]-1-formic acid benzyl ester (0.56g, add in DMF 1.43mmol) (14mL) solution two (TMS) Lithamide (2.86mL 1M solution, 2.86mmol), add then 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] _ piperazine]-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] _ piperazine]-(0.47g is in the solution of MeOH 1.17mmol) (40mL) for 1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 4 hours,, obtain title compound (0.35g) with mixture filtration over celite and concentrated.MS?234(M+1)。

Intermediate 14

1 '-methylspiro [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone The 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] _ piperazine]-2 ' (1 ' H)- Ketone

Steps A .7 '-chloro-l '-(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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] _ piperazine]-1-formic acid benzyl ester (0.20g, add in DMF 0.51mmol) (4mL) solution two (TMS) Lithamide (2.86mL 1M solution, 2.86mmol), add then 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] _ piperazine]- 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] _ piperazine]-(0.21g is in MeOH 0.48mmol) (10mL) solution for 1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 4 hours,, obtain title compound (0.14g) with mixture filtration over celite and concentrated.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

(5.0g, 21.4mol) (10.0g, benzene 30.0mmol) (100mL) solution was 75 ℃ of heating 48 hours for methyl acetate with (the inferior positive phosphorus base of triphenyl) with N-carbobenzoxy-(Cbz)-4-piperidone.Reactant is concentrated, and with ether dilution, filtering precipitation, filtrate (rinsate) concentrates.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

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, DMF 18.1mol) (120mL) solution.After 3 days, the reactant dilute with water is also used extracted with diethyl ether (4x).Merge organic phase,, filter and concentrating under reduced pressure through dried over mgso.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

(2.0M, 2.05mL 4.10mol) slowly are added to 0 ℃ 4-(2-methoxyl group-2-oxygen ethyl)-3 with trimethyl aluminium, 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 adds 4-{2-[(3-bromopyridine-2-yl) amino]-2-oxygen ethyl }-3, (1.91g is in THF 4.43mol) (15mL) solution for 6-dihydropyridine-1 (2H)-formic acid benzyl ester.0.5 after hour, (0.861mL 4.88mol), makes temperature of reaction keep below 10 ℃ simultaneously slowly to add 2-(TMS) oxyethyl group methyl chloride.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) two _ alkane (2 mL) mixture in add two (tri-butyl phosphine) palladium (O) (9mg, 0.018mmol).After 5 minutes, reactant is heated to 50 ℃.After 90 minutes, and adding two (tri-butyl phosphine) palladium (O) (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, and 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-(384mg 0.800mmol) adds trifluoroacetic acid (10mL) in the mixture in methylene dichloride (10mL) to the formic acid benzyl ester.After 3 hours, reactant is concentrated, and usefulness methylene dichloride (10mL) dilution and adding quadrol (720mg, 12.0mmol).After 18 hours, reactant is concentrated, 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.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 24 hours,, obtain title compound (130mg) with mixture filtration over celite and concentrated.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, and adding hexamethyl dimethyl silanyl Lithamide in tetrahydrofuran (THF) 16.4mmol) (90mL) solution (1.0M THF liquid, 18.1mL, 18.1mmol).After 1 hour, (2.19g 18.1mmol), stirs reactant 0.5 hour under this temperature, is warming to 25 ℃ then to add allyl bromide 98.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 add perosmic anhydride (0.45mL, 2.5% butanol solution), add sodium periodate (7.57g, water 35.4mmol) (37mL) solution then.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) be dissolved in acetate (100mL) and add 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), the organic layer drying of merging, and concentrated, obtain white solid (1.90g).This material is dissolved in acetonitrile (20mL), and (1.62g 12.0mmol) and with reactant is heated to 50 ℃ to add cupric chloride (II).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 also concentrates with 1N HCl washing, drying.Through silica gel chromatography purifying (100% methylene dichloride → 88% methylene chloride), obtain title compound (0.90g).MS?314.1(M+1)。

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

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

With chloro (chlorido) carbonic acid benzyl ester (10.5g, 61.3mmol) be added to the piperidin-4-yl ethyl acetate (10.0g, 58.4mmol) and yellow soda ash (46.2g is in methylene dichloride 438mmol) (320mL) solution.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 (5.0g is in tetrahydrofuran (THF) 16.4mmol) (90mL) solution 18.0mmol) to be added to 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester.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-oxygen-butyl] piperidines-1-formic acid benzyl ester

With perosmic anhydride (2.5wt.% t-butanol solution; 0.3mL, 0.001mmol) being added to 4-[1-(ethoxy carbonyl)-3-methyl fourth-3-alkene-1-yl] and (2.88g is in tetrahydrofuran (THF) 8.01mmol) (30mL) solution for piperidines-1-formic acid benzyl ester.(5.14g, water 24.0mmol) (26mL) solution is added to reaction mixture with sodium periodate.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 filters and the concentrated title compound that obtains through the S-WAT drying.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

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

(II) is (anhydrous with cupric chloride; 2.02g (2.48g is in acetonitrile 7.53mmol) (26mL) solution 15.05mmol) to be added to 4-(6-methyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester.Reaction mixture is in 90 ℃ of heating.After 18 hours, this mixture is cooled to room temperature and concentrates. resistates methylene chloride and 1N HCl.Mixture also concentrates the organic extract liquid that merges through dried over mgso with dichloromethane extraction (3x).Through silica gel chromatography purifying (100% methylene dichloride → 90% methylene chloride), 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) (1.45g is in ethanol 4.43mmol) (100mL) solution to be added to 4-(6-methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 24 hours, this mixture filtration over celite also concentrates, and 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

With N-bromine succinimide (52.0g, 292mmol) and benzoyl peroxide (2.0g, (82.0g is in tetracol phenixin 694mmol) (200mL) solution 8.0mmol) to be added to isopropenylbenzene.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.Filtrate concentrated and through vacuum distilling purifying (95-120 ℃, 10 torr).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 (1.94g is in tetrahydrofuran (THF) 6.65mmol) (35mL) solution 7.31mmol) to be added to 4-(2-methoxyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester.After 40 minutes, (1.08mL 7.31mmol) and with reaction mixture is warming to room temperature to benzene to add [1-(brooethyl) vinyl].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) being added to 4-[1-(methoxycarbonyl)-3-phenyl fourth-3-alkene-1-yl] and (2.11g is in tetrahydrofuran (THF) 5.19mmol) (20mL) solution for piperidines-1-formic acid benzyl ester.(3.33g, water 15.6mmol) (17mL) solution is added in the reaction mixture with sodium periodate.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

With hydrazine (3.31mL 104mmol) is added to 4-[1-(methoxycarbonyl)-3-oxo-3-phenyl propyl] (2.14g is in acetate 5.22mmol) (70mL) solution for piperidines-1-formic acid benzyl ester.With reaction mixture in 50 ℃ of heating.After 1 hour, 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

(II) is (anhydrous with cupric chloride; 1.27g (1.85g is in acetonitrile 4.73mmol) (16mL) solution 9.45mmol) to be added to 4-(3-oxo-6-phenyl-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester.Reaction mixture is heated to 90 ℃.After 2 hours, this mixture makes cool to room temperature and concentrates.Methylene dichloride is added in this enriched mixture, adds hydrochloric acid (the 1N aqueous solution) then.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), 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) (1.10g is in ethanol 2.82mmol) (50mL) solution to be added to 4-(3-oxo-6-phenyl-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 24 hours, this mixture filtration over celite also concentrates, and 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 (2.0g is in tetrahydrofuran (THF) 6.55mmol) (30mL) solution 7.20mmol) to be added to 4-(2-oxyethyl group-2-oxygen ethyl) piperidines-1-formic acid benzyl ester.After 40 minutes, add 2, and 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] (795mg is in ether 1.87mmol) (6mL) solution for piperidines-1-formic acid benzyl ester.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 add 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) are added to 4-[3-cyclopropyl-1-(ethoxy carbonyl) fourth-3-alkene-1-yl] (173mg is in tetrahydrofuran (THF) 0.45mmol) (2mL) solution for piperidines-1-formic acid benzyl ester.(290mg, water 1.35mmol) (1.5mL) solution is added to reaction mixture with sodium periodate.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

With hydrazine (0.3mL 9.6mmol) is added to 4-[3-cyclopropyl-1-(ethoxy carbonyl)-3-oxygen propyl group] (186mg is in acetate 0.48mmol) (7mL) solution for piperidines-1-formic acid benzyl ester.With reaction mixture in 50 ℃ of heating.After 1 hour, reaction mixture concentrates.Resistates neutralizes with the methylene dichloride dilution and with saturated sodium bicarbonate aqueous solution.Mixture dichloromethane extraction (3x), and will also concentrate 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, (134mg is in acetonitrile 0.38mmol) (16mL) solution 0.75mmol) to be added to 4-(6-cyclopropyl-3-oxo-2,3,4,5-tetrahydro pyridazine-4-yl) piperidines-1-formic acid benzyl ester.Reaction mixture is heated to 90 ℃.After 18 hours, this mixture is cooled to room temperature and concentrates.Methylene dichloride is added in this enriched mixture, adds hydrochloric acid (the 1N aqueous solution) then.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), 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; (54mg is in ethanol 0.15mmol) (20mL) solution 50mg) to be added to 4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 1 hour, this mixture filtration over celite also concentrates, and 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-diketone

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

Under 0 ℃, with potassium cyanide (2.79g, water 42.9mmol) (5mL) solution be added to 4-oxo-piperidine-1-formic acid benzyl ester (10.0g, 42.9mmol) and methylamine hydrochloride (2.90g is 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, fed 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

(5.74g, water 70.8mmol) (9mL) drips of solution is added to 4-cyano group-4-(methylamino) piperidines-1-formic acid benzyl ester, and (9.68g is in the acetate of hydrochloride 35.4mmol) (27mL) solution with potassium cyanide.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.Precipitated solid is filtered, wash with water, and drying under reduced pressure, title compound obtained.MS?318.1(M+1)。

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

With palladium (10% palladium charcoal; 1.0g) be added to 1-methyl-2,4-dioxo-1,3, (7.82g is in ethanol 24.6mmol) (100mL) solution for 8-thriazaspiro [4.5] decane-8-formic acid benzyl ester.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.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 also concentrates with washing with acetone.This mixture is with acetate dilution (50mL).With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 2 hours, this mixture filtration over celite, and concentrate the 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 ℃, (10.0g, (5.0g is in benzene 21.4mmol) (100mL) solution 30.0mmol) to be added to 4-oxo-piperidine-1-formic acid benzyl ester for methyl acetate with (the inferior phosphoranyl of triphenyl).After 1 hour, reaction mixture is heated to 75 ℃.After 48 hours, this mixture is concentrated and the adding ether.Concentrate with the precipitated solid filtering 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, (5.25g, N 18.2mmol) is in dinethylformamide (120mL) solution 18.2mmol) to be added to 4-(2-methoxyl group-2-oxygen ethylidene) piperidines-1-formic acid benzyl ester.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-l (2H)-formic acid benzyl ester

Under 0 ℃, (0.91g 12.61mmol) is added to 4-(2-methoxyl group-2-oxygen ethyl)-3,6-dihydropyridine-1 (2H)-formic acid benzyl ester (2.43g with trimethyl aluminium, 8.41mmol) and 3-bromopyridine-2-amine (1.60g is in ethylene dichloride 9.25mmol) (45mL) solution.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, (1.91g is in tetrahydrofuran (THF) 4.43mmol) (15mL) solution for 6-dihydropyridine-1 (2H)-formic acid benzyl ester.After 30 minutes, and adding [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), be then [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 the dicyclohexyl methylamine (42 μ L are 0.196mmol) in the solution of two _ alkane (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] and methyl }-2,2 ', 3,3 '-tetrahydrochysene-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-(50.0mg is in tetrahydrofuran (THF) 0.104mmol) (1mL) solution for the formic acid benzyl ester.After 40 minutes, (8.0 μ L 0.135mmol) and with reaction mixture slowly are warming to room temperature to add methyl iodide.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, and 1 ' H-spiral shell [1, the 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, and 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-pyridine]-1 '-(0.10g is in methylene dichloride 0.20mmol) (2mL) solution for the formic acid benzyl ester.After 2 hours, reaction mixture is concentrated.This spissated mixture is with methylene dichloride dilution (2mL) and add ethane-1,2-diamines (4mL).After 1 hour, reaction mixture concentrates and the adding saturated sodium bicarbonate aqueous solution.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 '-(73mg is 0.20mmol) with ethanol (10mL) dilution and add palladium (10% palladium charcoal for the formic acid benzyl ester; 100mg).With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.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 alkylsulfonyl 4-{[trifluoromethyl)] oxygen }-3,6-dihydropyridine-1 (2H)-formic acid Benzyl ester

Under-78 ℃, with n-Butyl Lithium (2.5M THF solution; 10.8mL (3.79mL is in tetrahydrofuran (THF) 27.0mmol) (37mL) solution 27.0mmol) to be added to diisopropylamine.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 to 4-oxo-piperidine-1-formic acid benzyl ester, and (5.26g is in tetrahydrofuran (THF) 22.5mmol) (50mL) solution.After 1 hour, add N-phenyl-two (fluoroform sulfimide) (8.85g, tetrahydrofuran (THF) 24.8mmol) (12mL) solution.This mixture is warming to 0 ℃.After 3 hours, this mixture also concentrates 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) at N, in the solution of dinethylformamide (12mL).(0.25g is 0.345mmol) and with this mixture heating up to 70 ℃ to add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture.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 ' ((0.42g is in ethyl acetate 1.3mmol) (4mL) solution for 2 ' H)-formic acid benzyl ester.Add palladium (10% palladium charcoal; 200mg) and with the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 3 hours, this mixture filtration over celite also concentrates, and obtains title compound (416mg).MS?293.2(M+1)。

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

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

Intermediate 26

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

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

With sodium hydroxide (173mg, 4.30mmol) be added to 2,2 '-(1-benzyl piepridine-4,4-two bases) oxalic acid diethyl ester (J Med.Chem.2004,47,1900-1918) (0.50g is in methyl alcohol 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

With urea (242mg, 4.03mmol) be 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, (242mg is 4.03mmol) and with this mixture heating up to 185 ℃ to add other urea.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, and it is complete until gas release to stir this suspension.This mixture is filtered and solid is washed with water, and concentrate, 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 acetate (250 μ L) be added to 9-benzyl-3,9-diaza spiro [5.5] hendecane-2, (0.38g is in ethanol 1.40mmol) (5mL) solution for the 4-diketone.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 18 hours, this mixture is filtered and concentrates, obtain the acetate (220mg) of title compound.MS?183.1(M+1)。

Intermediate 27

13,8-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), add ammonia (0.5M two _ alkane solution then; 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), 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 } (0.43g is in ethanol 1.14mmol) (20mL) solution for piperidines-1-t-butyl formate.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.After 18 hours, this mixture filters and concentrates, and 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

With trimethoxy-methane (230mg 2.16mmol) is added to the 4-{[(benzyloxy) carbonyl] amino }-(0.175g is in toluene 0.72mmol) (8mL) solution for 1-(tertbutyloxycarbonyl) piperidines-4-formic acid.Reaction mixture is heated to 90 ℃.After 18 hours, this mixture is concentrated.Through silica gel chromatography purifying (99% methylene chloride → 90% methylene chloride), 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 two _ alkane solution; 4mL 16.0mmol) is added to 4-oxo-1,3, and 8-thriazaspiro [4.5] last of the ten Heavenly stems-(60mg is in two _ alkane 0.24mmol) (6mL) solution for 1-alkene-8-t-butyl formate.After 18 hours, reaction mixture concentrates the hydrochloride that obtains title compound.MS?154.1(M+1)。

Intermediate 28

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

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

(16.0mL 114mmol) is added to 2, and (11.1g, 54.5mmol) with 2, (10.9g is 54.5mmol) in methylene dichloride (200mL) solution for the 3-propylene bromide for 4-dimethoxy-benzyl amine hydrochlorate with triethylamine.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 base) (2, the 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 } (71mg is in methylene dichloride 0.285mmol) (5mL) solution for penta-obtusilic acid.After 18 hours, 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, the 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) at N, in the solution in the dinethylformamide (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-6-(2, the 3-difluorophenyl)-1-(2, the 4-dimethoxy-benzyl)-2-oxygen Generation-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) (2.62 g, 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, (0.52g 0.61mmol), makes to be reflected at 40 ℃ of lasting again heating 48 hours to add other catalyzer.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, the 3-difluorophenyl)-oxo-2,3,4,7-tetrahydrochysene-1H-azepine _-3-aminocarbamic acid benzyl ester

Trifluoroacetic acid (60mL) is added to (3R)-6-(2, the 3-difluorophenyl)-1-(2, the 4-dimethoxy-benzyl)-2-oxo-2,3,4,7-tetrahydrochysene-1H-azepine _-(3.70g is in methylene dichloride 7.08mmol) (40mL) solution for 3-aminocarbamic acid benzyl ester.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, the 3-difluorophenyl)-2-oxa-azepan-3-base T-butyl carbamate

10% palladium charcoal (700mg) is added to (3R)-6-(2, the 3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydrochysene-1H-azepine _-3-aminocarbamic acid benzyl ester (2.6g, 6.98mmol) and tert-Butyl dicarbonate (5.03g is in toluene 23.0mmol) (200mL) solution.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.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 purified 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＝5.6?Hz，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(S5?9H)。

Step G:(3R, 6S)-6-(2, the 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) is added to (3R, 6S)-6-(2, the 3-difluorophenyl)-2-oxa-azepan-3-aminocarbamic acid tert-butyl ester (4.79g, in the suspension of toluene 14.1mmol) (250mL), 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, the 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-glutamate

Under 0 ℃, toward Boc-D-Glu-OBn (50.0g, 148.2mmol) in the solution of DCM (400ml) and MeOH (100ml) by other funnel dropping 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) add then DMAP (18.1g, 14.8mmol).After 24 hours, reactant is concentrated and, obtain title compound (48.20g, 72%) through silica gel chromatography purifying (10% → 60% ethyl acetate/hexane).MS?252.2(M+l-2Boc)。

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

Past-78 ℃ 1-benzyl 5-methyl N, N-two (tertbutyloxycarbonyl)-D-glutamate (48.2g, Et 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), and the salt water washing through dried over mgso, is filtered and concentratedly obtained N, and 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 ℃, add Nitromethane 99Min. (57.1mL, 1.05mol) and 1,1,3, the 3-tetramethyl guanidine (1.3mL, 10.5mmol).Stir after 30 minutes, the nitro aldolisation takes place fully, and under 0 ℃, (12.2mL, 158mmol), (22.0mL 158mmol), makes reactant be warming to RT to add triethylamine then to add SULPHURYL CHLORIDE.After 1 hour, add 4mL MsCl and 5.5mL triethylamine.After stirring 30 minutes in addition, 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 concentrate to obtain 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, the 3-difluorophenyl)-6-nitro -D-removes first leucine benzyl ester

With (2R, 5E)-2-[two (tertbutyloxycarbonyl) amino-6-nitro oneself-5-olefin(e) acid benzyl ester (34.0g, 73.2mmol), 2,3-difluorophenyl boric acid (28.9g, 183.0mmol) and water (4.62mL, 256.2mmol) solution in two _ alkane (240mL) was with argon-degassed 15 minutes.Add in this solution 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 through dried over mgso, filters and concentrate to obtain resistates, 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, the 3-difluorophenyl)-D-Methionin

With (5S)-N, N-(tertbutyloxycarbonyl)-5-(2, the 3-difluorophenyl)-6-nitro-D-go 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 55psi hydrogenation 18 hours again.Reactant with ethanol filtration over celite and concentrated, is obtained title compound (12.0g).MS459.2(M+1)。

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

Toward (5S)-N ², N ²-(tertbutyloxycarbonyl)-5-(2, the 3-difluorophenyl)-D-Methionin (22.0g, add in DCM 48.0mmol) (700mL) solution EDC (11.0g, 57.6mmol) and HOAT (3.27g, 24.0mmol), add then 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 of part (2.60g, 5.90mmol) 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 to concentrate, 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, the 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, the 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, 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) is 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, the 3-difluorophenyl) azepan-2-ketone

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

Under 0 ℃, with sodium hydride (60% mineral oil dispersion; 2.9g (10.0g, 65.3mmol) (12.7 g are 65.3mmol) at N, in the solution of dinethylformamide (100mL) with 4-bromine fourth acetate 71.8mmol) slowly to be added to (2, the 3-difluorophenyl) acetonitrile.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, the 3-difluorophenyl) ethyl hexanoate

With Raney nickel (2800, the diploma thing of water; With washing with alcohol (3x); 3.8g) (4.75g is in ethanol 17.8mmol) (100mL) solution to be added to 5-cyano group-5-(2, the 3-difluorophenyl) Valeric acid ethylester.Feed 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, the 3-difluorophenyl)-6-[(2, the 4-dimethoxy-benzyl) amino] caproic acid second Ester

With 2, the 4-dimethoxy benzaldehyde is added to 6-amino-5-(2, the 3-difluorophenyl) ethyl hexanoate, and (4.73g is in methyl alcohol 17.5mmol) (75mL) solution.Add acetate and reach pH5 until the pH of reaction mixture.After 30 minutes, and the adding 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, the 3-difluorophenyl)-6-[(2, the 4-dimethoxy-benzyl) amino] caproic acid

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

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

N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (3.65g 19.1mmol) is added to 5-(2, the 3-difluorophenyl)-6-[(2,4-dimethoxy-benzyl) amino] (8.58g is in acetonitrile 17.3mmol) (346mL) solution for Sodium n-caproate.After 2 hours, add hydrochloric acid (4.0M two _ alkane solution; 13.0mL; 52.0mmol).After 16 hours, add other N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (3.24g, 16.9mmol), the I-hydroxybenzotriazole hydrate (1.0g, 6.53mmol) and triethylamine (4.83mL, 34.6mmol).After 16 hours, reaction mixture concentrates.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), obtain title compound (4.72g).MS?376.1(M+1)。

Step F: (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl)-1-(2, the 4-dimethoxy The base benzyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2,3-two fluorobenzene Base)-1-(2, the 4-dimethoxy-benzyl) azepan-2-ketone

Under-78 ℃, the lithium diisopropylamine (solution of 1.8M THF, heptane and ethylbenzene; 22.9mL, 41.3mmol) be added to that 6-(2, the 3-difluorophenyl)-(3.87g is in tetrahydrofuran (THF) 10.3mmol) (38mL) solution for 1-(2, the 4-dimethoxy-benzyl) azepan-2-one.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, the 3-difluorophenyl) azepan-2-ketone

(35mL) is added to (3S with trifluoroacetic acid, 6S)-3-allyl group-6-(2, the 3-difluorophenyl)-1-(2, the 4-dimethoxy-benzyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl)-(3.39g is 8.15mmol) in the solution in methylene dichloride (25mL) for 1-(2, the 4-dimethoxy-benzyl) azepan-2-ketone.2.5 after hour, reaction mixture concentrates.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 → 97% methylene chloride), obtain racemize trans-compound (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone, and racemize cis compound (35,6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone and (3R, 6R)-mixture of 3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone.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, the 3-difluorophenyl) azepan-2-sulphur Ketone

With trifluoroacetic acid (5mL, 49.6mmol) be added to (3R, 6S)-(680mg is 1.91mmol) in the solution of methylene dichloride (10mL) for 6-(2, the 3-difluorophenyl)-2-sulphur oxa-azepan-3-aminocarbamic acid tert-butyl ester.After 1 hour, 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, the 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) (466mg's piperidines-1-formyl chloride 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), obtain title compound (685mg).MS?501.0(M+1)。

Intermediate 35

2-amino-1-cyclopropyl ethanol

Under 0 ℃, with the TMS prussiate (8.68mL, 65.1mmol) and zinc iodide (II) (10mg, methylene dichloride 0.05mmol) (5mL) drips of solution is added to cyclopanecarboxaldehyde, and (4.05mL is in methylene dichloride 54.2mmol) (30mL) solution.After interpolation finishes, this mixture is warming to room temperature.1.5 after hour, this mixture concentrates.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.After interpolation finished, this mixture was warming to room temperature.After 1 hour, this mixture order water (2.5mL), 15% sodium hydroxide solution (2.5mL) and water (7.5mL) are handled.Polity is filtered and, filtrate is concentrated, obtain title compound (0.79g) with washed with dichloromethane (3x). 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, prepare the intermediate of table 1.

Table 1

Intermediate 44

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

(5.27g 41.8mmol) is added to ammonia solution (2M methanol solution with 2-(2,2, the 2-trifluoroethyl) oxyethane; 170mL 340mmol) also is heated to 60 ℃ with this solution.1.25 after hour, make this mixture cool to room temperature and be concentrated into the 20mL volume.HCl (4M two _ alkane liquid; 12mL 48mmol) slowly adds and this mixture concentrated obtains white solid (4.0g), and its purity is 85%, wherein also comprises 15% two rapid by products.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 _

With the anhydrous salt acid gas feed 4-amino-3-hydroxybutyric acid (0.91g, 7.61mmol) in the suspension in methyl alcohol (150mL), saturated and in stirring at room until this solution.After 18 hours, concentrate this solution, obtain 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 two _ alkane solution; 0.4mL (2.8g extremely refluxes in Virahol 21.03mmol) (50mL) solution and with this mixture heating up 1.6mmol) to be added to 4-amino-3-beta-hydroxymethyl butyrate.After 18 hours, add other hydrochloric acid (4.0M two _ alkane solution, 0.4mL, 1.6mmol).After 40 hours, 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 _

With 2-amino-4,4, (11.7g 52.8mmol) is added in ethanol (100mL) solution of saturated HCl and is heated to 85 ℃ the 4-trifluoroacetic acid.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) being added to 1-oxyethyl group-4,4,4-three fluoro-1-oxygen fourth-2-amine chlorinations _ (205mg is in ether 0.928mmol) (15mL) solution.1.5 after hour, this mixture order water (0.085mL), 15% sodium hydroxide (0.085mL), water (0.255mL) is handled, and filtration over celite and concentrated obtains title compound then.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

(52mg, (100mg is in tetrahydrofuran (THF) 0.46mmol) (1mL) solution 0.46mmol) to be added to the imino-tert-Butyl dicarbonate with potassium tert.-butoxide.After 5 minutes, and adding 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

(114mg, (115mg is 0.40mmol) in the solution of acetone (0.8mL), water (0.2mL) and Glacial acetic acid (20 μ L) 0.72mmol) to be added to (3-methyl but-2-ene-1-yl) imino-tert-Butyl dicarbonate for potassium permanganate.After 4 hours, with saturated sodium sulfite aqueous solution termination reaction.This mixture is transferred to pH5 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 (two _ alkane solution of 4M; 1.0mL (102mg in methyl alcohol 0.32mmol) (3mL) solution, and is warming to room temperature with this mixture 4.0mmol) to be added to (3-hydroxy-3-methyl-2-oxygen-butyl) imino-diacetic dimethyl dicarbonate butyl ester.2.5 after hour, reaction mixture concentrates the hydrochloride that obtains title compound.MS?118.0(M+1)。

Intermediate 49

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

Steps A: (3R, 6S)-6-[2, the 3-difluorophenyl)-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)-6-(2, the 3-difluorophenyl)-2-sulphur oxa-azepan-3-yl] t-butyl carbamate (2.50g, 7.01mmol), 4,4,4-three fluoro-2-hydroxyl fourth-1-amine chlorinations _ (4.62g, 25.7mmol) and triethylamine (4.40mL is 31.6mmol) in the solution 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

(7.92g 21.0mmol) is added to { (3R, 65)-6-(2 with the dichromic acid pyridine, the 3-difluorophenyl)-2-[(4,4,4-three fluoro-2-hydroxybutyls) imino-] azepan-3-yl } (3.27g is in acetonitrile 7.01mmol) (70mL) solution for the t-butyl carbamate crude product.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), 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, the 3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under 0 ℃, with diisobutyl aluminium hydride (1.0M hexane liquid; 3.77mL, 3.77mmol) be added to [(6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl] (328 mg are in methylene dichloride 0.75mmol) (12mL) solution for methyl acetate.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), obtain title compound (218mg).MS?408.1(M+1)。

Intermediate 66

2-[(6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under 0 ℃, with Acetyl Chloride 98Min. (24 μ L, 0.344mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (70mg, 0.172mmol) and triethylamine (48 μ L are 0.344mmol) in the 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), obtain title compound (64mg).MS?450.2(M+1)。

Intermediate 67

(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-methoxy ethyl)-6,7,8, the 9-tetrahydrochysene- 5H-imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (19mg, 0.047mmol) and methyl iodide (3.0 μ L, 0.051mmol) tetrahydrofuran (THF) (0.5mL) solution in, 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), obtain title compound (6mg).MS?422.1(M+1)。

Intermediate 68

(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under-78 ℃, with diisobutyl aluminium hydride (1.0M dichloromethane solution; 0.81mL, 0.807mmol) be added to [(6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine _-the 3-yl] (187mg is in methylene dichloride 0.403mmol) (10mL) solution for the acetate isopropyl esters.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), obtain title compound (120mg).MS?406.2(M+1)。

Intermediate 69

(6S, 9R)-6-(2, the 3-difluorophenyl)-3-[2-(dimethylamino) ethyl]-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

With sodium cyanoborohydride (12mg, 0.185mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid 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 pH5 with acetate.After 2 hours, with this solution concentration.Through silica gel chromatography purifying (100% methylene dichloride → 92% methylene chloride), obtain title compound (45mg).MS435.2(M+1)。

Intermediate 70

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

Under 0 ℃, with (diethylamino) sulfur trifluoride (92 μ L, 0.696mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(94mg is 0.232mmol) in the solution in methylene dichloride (10mL) for the 9-aminocarbamic acid tert-butyl ester.After 2 hours, add saturated sodium bicarbonate aqueous solution also with this mixture dichloromethane extraction (2x).The organic extract liquid that merges filters and concentrates through the S-WAT drying.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride), obtain title compound (67mg).MS?428.2(M+1)。

Intermediate 71

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

Methyl-magnesium-bromide (3.0M ether solution; 0.70mL, 2.10rnmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(85mg is 0.210mmol) in the solution in tetrahydrofuran (THF) (5mL) for the 9-aminocarbamic acid tert-butyl ester.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 filters and concentrates through the S-WAT drying.Through silica gel chromatography purifying (100% methylene dichloride → 95% methylene chloride), obtain title compound (73mg).MS?422.2(M+1)。

Intermediate 72

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

Steps A: (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen propyl group)-6,7,8,9-four Hydrogen-5H-imidazo [1,2-a] azepine _-the 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 _-the 9-aminocarbamic acid tert-butyl ester (85mg; 0.202mmol) in the solution 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 filters and concentrates through the S-WAT drying.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, the 3-difluorophenyl)-3-(2-hydroxy-2-methyl propyl group) -6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Methyl-magnesium-bromide (3.0M ether solution; 0.49mL, 1.45mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2-oxygen propyl group)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (61mg is in tetrahydrofuran (THF) 0.145mmol) (5mL) solution for t-butyl carbamate.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 filters and concentrates through the S-WAT drying.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride), obtain title compound (36mg).MS?436.2(M+1)。

Intermediate 73

(6S, 9R)-6-(2, the 3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazoles And [1,2-a] azepine _-the 9-yl] t-butyl carbamate

With tin anhydride (1.73g, 15.63mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-and 3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (2.95g, in two _ alkane 7.82mmol) (200mL) solution, and with the extremely backflow of this mixture heating up.After 8 hours, reaction mixture filters and concentrates.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, the 3-difluorophenyl)-3-(2,2,2-three fluoro-1-hydroxyethyls)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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 add purified (6S, 9R)-6-(2, the 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, the 3-difluorophenyl)-3-(2,2,2-three fluoro-1-methoxy ethyls)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-3-(2,2,2-three fluoro-1-hydroxyethyls)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (0.68g, 1.47mmol) and methyl iodide (92.0 μ L are 1.47mmol) in the 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, the 3-difluorophenyl)-3-(hydroxymethyl)-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

With sodium borohydride (19.0mg, 0.51mmol) be added to (6S, 9R)-6-(2; the 3-difluorophenyl)-and 3-formyl radical-6,7,8; 9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(100mg is in tetrahydrofuran (THF) 0.26mmol) (3mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(methoxymethyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-and 3-(hydroxymethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (160mg, 0.41mmol) and methyl iodide (51.0 μ L are 0.81mmol) in the 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, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under 0 ℃; with (diethylamino) sulfur trifluoride (14 μ L; 0.10mmol) be added to (6S; 9R)-6-(2, the 3-difluorophenyl)-3-formyl radical-6,7; 8; 9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(20mg is 0.05mmol) in the solution in methylene dichloride (1mL) for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(130mg is in tetrahydrofuran (THF) 0.33mmol) (3mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-3-formyl radical-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(60mg is in tetrahydrofuran (THF) 0.15mmol) (1mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-6,7,8,9-four Hydrogen-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under 0 ℃, with methyl iodide (9.0 μ L, 0.15mmol) be added to (6S, 9R)-3-[cyclopropyl (hydroxyl) methyl]-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid 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, the 3-difluorophenyl)-3-(1-methoxymethyl)-6,7,8, the 9-tetrahydrochysene- 5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Under 0 ℃, with methyl iodide (6.0 μ L, 0.10mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid 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, shared 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, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazoles And [1,2-a] azepine _-the 9-yl] t-butyl carbamate

With the dichromic acid pyridine (0.96g, 2.55mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydrochysene～5H-imidazo [1,2-a] azepine _-(0.52g is in acetonitrile 1.28mmol) (10mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9 -tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-6; 7,8,9-tetrahydrochysene-5H-imidazo [1; 2-a] azepine _-(22mg in tetrahydrofuran (THF) 0.05mmol) (1mL) solution, and is warming to room temperature with reaction mixture to the 9-aminocarbamic acid tert-butyl ester.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), add immediately then triethylamine (0.20mL, 1.40mmol).After 23 hours, reactant is filtered and use methanol wash, concentrate then.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), obtain title compound (85mg).MS?422.2(M+1)。

Intermediate 85

(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2,2-three fluoro-1-hydroxyls-1-methyl second Base)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] the carboxylamine uncle Butyl ester

With (trifluoromethyl) trimethyl silane (0.273mL, 1.85mmol) and tetrabutyl ammonium fluoride (1.0M tetrahydrofuran (THF) liquid; 74 μ L, 0.074mmol) be added in proper order (6S, 9R)-3-ethanoyl-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(150mg is in tetrahydrofuran (THF) 0.37mmol) (1mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine

With methylsulfonic acid (77 μ L, 1.19mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-aminocarbamic acid tert-butyl ester (100mg, in methyl alcohol 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)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] azepine _-the 3-methyl-formiate

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

With SODIUM PHOSPHATE, MONOBASIC (127mg; 0.92mmol) and Textone (42mg; 0.46mmol) be added to (6S; 9R)-6-(2, the 3-difluorophenyl)-3-formyl radical-6,7; 8; 9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(45mg is 0.12mmol) in the solution in tetrahydrofuran (THF) (0.8mL), water (0.8mL), the trimethyl carbinol (0.2mL) and 2-methyl-2-butene (0.2mL) for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-methyl-formiate

With (TMS) two azomethanes (2.0M ether solution; 173 μ L, 0.35mmol) be added to (6S, 9R)-the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(47mg is 0.12mmol) in the solution in methylene dichloride (1.5mL) and methyl alcohol (0.5mL) for 3-formic acid.After 1 hour, add other (TMS) two azomethanes (2.0M ether solution; 50 μ L, 0.10mmol).After 4 hours, reaction mixture is concentrated.MS?422.2(M+1)。

Intermediate 95

[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8, the 9-tetrahydrochysene- 5H-imidazo [1,2-a] azepine _-the 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 through 15 minutes, 0.26mmol) and (6S, 9R)-and the 9-[(tertbutyloxycarbonyl) amino]-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine _-(54mg is in ether 0.13mmol) (0.9mL) solution for the 3-methyl-formiate.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, 9R)-the 3-tertiary butyl-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazoles And [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)-2-sulphur oxa-azepan-3-yl] t-butyl carbamate (10mg, 0.028mmol), 1-amino-3, the hydrobromate (11mg of 3-dimethyl butyrate-2-ketone, 0.056mmol) and triethylamine (10 μ L are 0.07mmol) in the solution in ethanol (1mL).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), obtain title compound (14mg).MS?420.2(M+1)。

Intermediate 97

[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methyl-propyl)-6,7,8,9 -tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(25mg is in tetrahydrofuran (THF) 0.062mmol) (1mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8, the 9-tetrahydrochysene- 5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate and [(6S.9R)-6- (2, the 3-difluorophenyl)-3-(1-ethyl-1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 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, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine _-(100mg is 0.237mmol) in the solution in tetrahydrofuran (THF) (4mL) for the 3-methyl-formiate.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 other ethylmagnesium bromide (3M ether solution again; 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 through silica gel chromatography purifying (100% methylene dichloride → 95% dichloromethane/ethyl acetate), 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate (62mg) MS420.2 (M+1) and [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-ethyl-1-hydroxyl cyclopropyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] mixture of t-butyl carbamate (18mg) MS 450.2 (M+1).

Intermediate 100

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

Steps A: (2Z, 3R, 6S)-and 6-(2, the 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)-6-(2, the 6-difluorophenyl)-2-sulphur oxa-azepan-3-yl] t-butyl carbamate (353mg, 0.99mmol), 4,4,4-three fluoro-2-hydroxyl fourth-1-amine chlorinations _ (498mg, 2.77mmol) and triethylamine (0.61mL is 4.36mmol) in the solution 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, the 6-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate

(2.24g 5.94mmol) is added to { (2Z, 3R with the dichromic acid pyridine, 6S)-and 6-(2, the 6-difluorophenyl)-2-[(4,4,4-three fluoro-2-hydroxybutyls) imino-] azepan-3-yl } (461mg is in acetonitrile 0.99mmol) (20mL) solution for t-butyl carbamate.After 18 hours, this mixture filters 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 (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, the 6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 3-yl]-the 1-methyl ethoxy } ethanol

With methylsulfonic acid (78 μ L, 1.19mmol) be added to [(6S, 9R)-6-(2, the 6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-[α]] azepine _-the 9-yl] t-butyl carbamate (104mg, in ethylene glycol 0.24mmol) (4mL) solution, and with this mixture heating up to 60 ℃.After 18 hours, reaction mixture concentrates.Add saturated sodium bicarbonate aqueous solution, and, the organic extract liquid that merges is washed with saturated brine,, filter also concentrated through dried over sodium sulfate with this mixture dichloromethane extraction (3x).MS366.1(M+1)。

Intermediate 104

2-[(6S, 9R)-9-amino-6-(2, the 6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-miaow Azoles also [1,2-a] azepine _-the 3-yl]-propan-2-ol

According to preparing the method that intermediate 103 is described, water replaces ethylene glycol intermediate 104.MS?322.1(M+1)。

Intermediate 105

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

Substantially according to preparing the method preparation that intermediate 100 is described.MS?428.2(M+1)。

Intermediate 106

[(6S, 9R)-6-cyclohexyl-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-miaow Azoles also [1,2-a] azepine _-the 9-yl] t-butyl carbamate

Substantially according to preparing the method preparation that intermediate 100 is described.MS?416.3(M+1)。

Intermediate 107

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

Substantially according to preparing the method preparation that intermediate 100 is described.MS?424.1(M+1)。

Intermediate 108

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

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

With a hydrazine hydrate (2.23mL, 46.0mmol) be added to (3R, 6S)-(546mg is in methyl alcohol 1.53mmol) (25mL) solution for 6-(2, the 3-difluorophenyl)-2-sulphur oxa-azepan-3-aminocarbamic acid tert-butyl ester.After 30 minutes, this mixture 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 the S-WAT drying, obtains title compound (548mg).MS?355.2(M+1)。

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

With triethylamine (0.259mL, 1.86mmol) be added to (3R, 65)-6-(2, the 3-difluorophenyl)-the 2-hydrazine pitch basic azepan-3-aminocarbamic acid tert-butyl ester (548mg, 1.55mmol), 3,3,3-trifluoroacetic acid (0.205mL, 2.32mmol), (356mg, 1.86mmol) (253mg is 1.86mmol) in the solution in methylene dichloride (55mL) with 1-hydroxyl-7-azepine benzotriazole for 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.After 18 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through the S-WAT drying.Through silica gel chromatography purifying (100% methylene dichloride → 96% methylene chloride), 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H- [1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate

Steps A: 3-allyl group-6-(2, the 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) (426mg is 1.61mmol) in the suspension in toluene (10mL) to be added to 3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone.After 3 hours, reaction mixture is heated to 45 ℃.After 30 minutes, 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, the 3-difluorophenyl) azepan-2-ketone hydrazone

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

Step C:9-allyl group-6-(2, the 3-difluorophenyl)-3-(2,2, the 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) (285mg is 1.02mmol) with 3,3 for azepan-2-ketone hydrazone, (90 μ L are 1.02mmol) in the solution in acetonitrile (25mL) for the 3-trifluoroacetic acid.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, and the 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8, the 9-tetrahydrochysene -5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate

With sodium periodate (191mg, 0.89mmol) in water (7.77mL) is added to 9-allyl group-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _ (83mg is in tetrahydrofuran (THF) 0.224mmol) (7mL) solution.With yellow soda ash (0.5M; 0.20mL) reaction mixture transferred to pH7.5 and add 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 the pH of solution is transferred to pH5 with hydrochloric acid.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 according to the method for intermediate 112 preparations, prepare the intermediate of 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, the 3-difluorophenyl)-3-sec.-propyl-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl]-4-(2-oxo-2,3-dihydro-1H-imidazoles And [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Steps A: N-{ (3R, 6S)-6-(2, the 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) and 1-amino-3-methyl fourth-2-alcohol (122mg is in methyl alcohol 1.18mmol) (7mL) solution.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 (164 mg) 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-four Hydrogen-H-imidazo [1,2-a] azepine _-the 9-yl]-4-(2-oxo-2, the 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) piperidines-1-methane amide trifluoroacetate (164mg, 0.206mmol) and acetate (24 μ L are 0.411mmol) in the solution in methylene dichloride (10mL).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 filters and concentrates through the S-WAT drying.Through silica gel chromatography purifying [100% methylene dichloride → 93% methylene chloride)], obtain title compound (76mg).MS?550.2748(M+1)。

Substantially according to the preparation method of embodiment 1, prepare the embodiment compound in the table 7.

Table 7

Embodiment 10

N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl]-4-(2-oxo-2,3-dihydro -1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Steps A: (6S, 9R)-6-(2, the 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 two _ alkane liquid; 3mL, 12.0mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate (113mg, 0.261mmol) 1, in 4-two _ alkane (3mL) solution.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, the 3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl]-4-(the 2-oxo- 2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Under 0 ℃, with triethylamine (43 μ L, 0.310mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(tetrahydrofuran (THF)-3-yl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-dihydrochloride (42mg of 9-amine, 0.103mmol) and the 4-chloroformate nitrophenyl ester (21mg is 104mmol) in the solution in tetrahydrofuran (THF) (3mL).After 30 minutes, add 2-oxo-1-piperidines _-4-base-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-_ dichloride (45mg, 0.155mmol), (43 μ L 0.310mmol) and methylene dichloride (3mL), and make this mixture be warming to room temperature to triethylamine.After 18 hours, 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)。

Substantially according to the preparation method of embodiment 10, prepare the embodiment compound in the table 8.

Table 8

Embodiment 47

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

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

With hydrochloric acid (4.0M two _ alkane liquid; 4.0mL, 16.0mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(100mg is in two _ alkane 0.224mmol) (2mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl]-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine-1-methane amide

Under 0 ℃, (94 μ L 0.673mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (94mg, 0.224mmol) and the 4-chloroformate nitrophenyl ester (45mg is 0.224mmol) in the solution in tetrahydrofuran (THF) (3mL).After 1 hour, add 2 '-oxo-1 ', 2 '-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], 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)。

Substantially according to the preparation method of embodiment 47, prepare the embodiment compound in the table 9.

Table 9

Embodiment 61

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(2-hydroxyethyl)-1-methyl Ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1 '-methyl -2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] -1-methane amide

Under 0 ℃, with triethylamine (14 μ L, 0.104mmol) be added to 2-{1-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl]-the 1-methyl ethoxy } ethanol (38mg, 0.104mmol) and the 4-chloroformate nitrophenyl ester (21mg is 0.104mmol) in the solution in tetrahydrofuran (THF) (3mL).After 1 hour, add 1 '-methylspiro [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone (and 23mg, 0.104mmol) and triethylamine (42 μ L 0.31mmol), and are warming to room temperature with this mixture.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), obtain title compound (41mg).MS?609.3013(M+1)。

Embodiment 62

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

Trifluoroacetic acid (2mL) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(50mg is 0.112mmol) in the solution in methylene dichloride (2mL) for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, (16 μ L 0.11mm0l) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (38mg, 0.11mmol) and the 4-chloroformate nitrophenyl ester (23mg is 0.11mmol) in the solution in tetrahydrofuran (THF) (2mL).After 1 hour, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 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), 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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, triethylamine (52 μ L, 0.38mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (0.14g, 0.42mmol) and the 4-chloroformate nitrophenyl ester (93mg is 0.46mmol) in the solution of in tetrahydrofuran (THF) (10mL).After 30 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 101mg, 0.46mmol) and triethylamine (126 μ L 1.25mmol), and are warming to room temperature with this mixture.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), 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)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] azepine _-the 3-yl] propan-2-ol

With trifluoroacetic acid (2mL, 26.9mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (100mg is 0.24mmol) in the solution in methylene dichloride (3mL) for t-butyl carbamate.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, the 3-difluorophenyl)-3-(1-methoxyl group-1-first The base ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-1- Methane amide

Under 0 ℃, triethylamine (31 μ L, 0.23mmol) be added to 2-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl] propan-2-ol (76mg, 0.24mmol) and the 4-chloroformate nitrophenyl ester (50mg is 0.25mmol) in the solution in tetrahydrofuran (THF) (3mL).After 20 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 57mg, 0.26mmol) and triethylamine (99 μ L 0.71mmol), and are warming to room temperature with this mixture.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), 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)。

Substantially according to the preparation method of embodiment 62-64, prepare the embodiment compound in the table 10.

Table 10

Embodiment 95

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

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

With titanium ethanolate (IV) (239mg; 1.05mmol) be added to [(6S; 9R)-6-(2; the 3-difluorophenyl)-and 3-formyl radical-6,7,8; 9-tetrahydrochysene-5H-imidazo [1; 2-a] azepine _-the 9-yl] and t-butyl carbamate (205mg, 0.524mmol) and (R)-2-methylpropane-2-thionyl amines (79mg, 0.655mmol) solution 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), 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 _-the 9-yl] amino T-butyl formate

Under 0 ℃; methyl-magnesium-bromide (0.24mL; 0.71mmol) be added to [(6S; 9R)-3-{ (E)-[tertiary butyl sulfinyl (imino-) methyl] }-6-(2, the 3-difluorophenyl)-6,7; 8; 9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (117mg is in the solution of tetrahydrofuran (THF) 0.24mmol) (4mL) for t-butyl carbamate.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), obtain title compound (144mg).MS?511.2(M+1)。

Step C:N-{1[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl]-2-methylpropane-2-sulfinyl Amine

With trifluoroacetic acid (1mL; 13.5mmol) be added to [(6S; 9R)-and 3-{1-[(tertiary butyl sulfinyl) amino] ethyl }-6-(2; the 3-difluorophenyl)-6; 7,8,9-tetrahydrochysene-5H-imidazo [1; 2-a] azepine _-the 9-yl] (144mg is 0.28mmol) in the solution in methylene dichloride (5mL) for t-butyl carbamate.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, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl } -2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ Piperazine]-the 1-methane amide

Under 0 ℃, with triethylamine (14 μ L, 0.097mmol) be added to N-{1-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl] ethyl }-2-methylpropane-2-sulfinyl amine (40mg, 0.097mmol) and the 4-chloroformate nitrophenyl ester (20mg is 0.097mmol) in the solution in tetrahydrofuran (THF) (3mL).After 10 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (hydrochloride of 1 ' H)-ketone (and 43mg, 0.146mmol) 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), obtain title compound (65mg).MS?656.3(M+1)。

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

Hydrochloric acid (4.0M two _ alkane liquid; 0.50mL, 2.0mmol) be added to N-[(6S, 9R)-3-{1-[(tertiary butyl sulfinyl) amino] ethyl }-6-(2; the 3-difluorophenyl)-6; 7,8,9-tetrahydrochysene-5H-imidazo [1; 2-a] azepine _-the 9-yl]-2 '-oxo-1 '; 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1; 3] piperazine]-(65mg is in methyl alcohol 0.099mmol) (7mL) solution for the 1-methane amide.After 16 hours, 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, the 3-difluorophenyl)-3-[1-(dimethylamino) ethyl]- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Sodium cyanoborohydride (5.0mg, 0.080mmol) be added to N-{ (6S, 9R)-3-(1-amino-ethyl)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide (15mg, 0.023mmol) and formaldehyde (37% methanol solution; 27 μ L are in methyl alcohol 0.363mmol) (1mL) solution.After 16 hours, 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, the 3-difluorophenyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

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

Methylsulfonic acid (0.30mL, 4.63mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] t-butyl carbamate (50mg, 0.115mmol) and sodiumazide (170mg is 2.62mmol) in the solution in chloroform (10mL).After 1 hour, add other methylsulfonic acid (0.95mL, 14.65mmol).After 16 hours, 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)-(2,3-two for 6- Fluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-1- Methane amide

Under 0 ℃, with triethylamine (15 μ L, 0.11mmol) be added to (6S, 9R)-3-(1-azido--1-methylethyl)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (38mg, 0.11mmol) and the 4-chloroformate nitrophenyl ester (22mg is 0.11mmol) in the 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] _ piperazine]-2 ' (hydrochloride of 1 ' H)-ketone (and 50mg, 0.171mmol) and triethylamine (40 μ L 0.287mmol), and are warming to room temperature with this mixture.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), obtain title compound (37mg).MS?592.2(M+1)。

Step C:N-{ (6S, 9R)-3-(1-amino-1-methylethyl)-6-(2, the 3-difluoro Phenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl-2 '-oxo -1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-first Acid amides

Palladium (10% palladium charcoal; 10mg) be added to N-[(6S, 9R)-3-(1-azido--1-methylethyl)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-(37mg is in ethyl acetate 0.063mmol) (5mL) solution for the 1-methane amide.With the reaction vessel degassing and recharge nitrogen (3x), recharge hydrogen (1 normal atmosphere) then.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

Sodium cyanoborohydride (6.0mg 0.093mmol) is added to N-[(6S, 9R)-and 3-(1-amino-1-methylethyl)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl]-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-hydrochloride of 1-methane amide (18mg, 0.027mmol) and formaldehyde (37% methanol solution; 32 μ L are 0.427mmol) in the solution in methyl alcohol (1.5mL).After 1 hour, 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, the 3-difluorophenyl)-9-{[2 '-oxo-1 ', 2 '-dihydro- The 1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine-1-yl) carbonyl] amino }- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl)-the 1-methyl ethoxy] Ethylhexoate

Under 0 ℃, (28 μ L 0.20mmol) are added to N-{ (6S with triethylamine, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-1-methane amide (61mg, 0.10mmol) and Acetyl Chloride 98Min. (14.0 μ L are 0.204mmol) in the solution in methylene dichloride (5mL).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, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Steps A: N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methyl Ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl-1 '-(first The oxygen ylmethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3 -d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, with triethylamine (18 μ L, 0.126mmo1) be added to 2-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl] propan-2-ol (45mg, 0.140mmol) and the 4-chloroformate nitrophenyl ester (31mg is 0.154mmol) in the solution in tetrahydrofuran (THF) (4mL).After 1 hour, add 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 41mg, 0.154mmol) and triethylamine (39 μ L 0.378mmol), and are warming to room temperature with this mixture.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], obtain title compound (69mg).MS?611.2780(M+1)。

Embodiment 101

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

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

Under 0 ℃, with triethylamine (18 μ L, 0.126mmol) be added to 2-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl] propan-2-ol (45mg, 0.140mmol) and the 4-chloroformate nitrophenyl ester (31mg is 0.154mmol) in the solution in tetrahydrofuran (THF) (4mL).After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 41mg, 0.154mmol) and triethylamine (39 μ L 0.378mmol), and are warming to room temperature with this mixture.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], obtain title compound (69mg).MS?581.2690(M+1)。

Substantially according to the preparation method of embodiment 101, prepare the embodiment compound in the table 11.

Table 11

Embodiment 104

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

Hydrochloric acid (4.0M two _ alkane liquid; 2.0rnL, the te7 tertiary butyl in the solution that 8.0mmol) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-aminocarbamic acid ester (100mg, 0.224mmol) in two _ alkane (1mL).After 1 hour, reaction mixture concentrates the hydrochloride that obtains title compound.MS?346.1(M+1)。

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

Under 0 ℃, (94 μ L 0.673mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (94mg, 0.224mmol) and the 4-chloroformate nitrophenyl ester (45mg is 0.224mmol) in the solution in tetrahydrofuran (THF) (3mL).After 1 hour, add 8-oxo-7-piperidines _-4-base-8,9-dihydro-7H-purine-3-_ dichloride (66mg, 0.224mmol) and triethylamine (94 μ L 0.673mmol), and are warming to room temperature with this mixture.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)。

Substantially according to the preparation method of embodiment 104, prepare the embodiment compound in the table 12.

Table 12

Embodiment 109

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-(6-fluoro-2-hydrogen generation- 2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Hydrochloric acid (4.0M two _ alkane liquid; 2.0mL, 8.0mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(20mg is in two _ alkane 0.045mmol) (1mL) solution for the 9-aminocarbamic acid tert-butyl ester.After 1 hour, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.1(M+1)。

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

Under 0 ℃, (19 μ L 0.135mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (18.8mg, 0.045mmol) and the 4-chloroformate nitrophenyl ester (9.0mg is 0.045mmol) in the solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 6-fluoro-2-oxo-1-piperidines _-4-base-2,3-dihydro-1H-imidazo [4,5-δ] pyridine-4-_ dichloride (14mg, 0.045mmol) and triethylamine (19 μ L 0.135mmol), and are warming to room temperature with this mixture.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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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 two _ alkane liquid; 2.0mL, 8.0mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(20mg is in two _ alkane 0.045mmol) (1mL) solution for the 9-aminocarbamic acid tert-butyl ester.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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-(5-oxo-3 -phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl) piperidines-1-methane amide

Under 0 ℃, (19 μ L 0.135mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (18.8mg, 0.045mmol) and the 4-chloroformate nitrophenyl ester (9.0mg is 0.045mmol) in the 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 are warming to room temperature with this mixture.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

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

Under 0 ℃, (19 μ L 0.135mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (18.8mg, 0.045mmol) and the 4-chloroformate nitrophenyl ester (9.0mg is 0.045mmol) in the 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 are warming to room temperature with this mixture.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, the 3-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-first The base ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-(2 -oxo-1,4-dihydroquinazoline-3 (2H)-1-yl) piperidines-1-methane amide

Under 0 ℃, with triethylamine (5.0 μ L, 0.037mmol) be added to 2-{1-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl]-the 1-methyl ethoxy } ethanol (15.0mg, 0.041mmol) and the 4-chloroformate nitrophenyl ester (9.0mg is 0.045mmol) in the solution 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 are warming to room temperature with this mixture.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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-(2, the 4-dioxo alkyl imidazole -1-yl) piperidines-1-methane amide

Trifluoroacetic acid (2mL) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(50mg is 0.112mmol) in the solution in methylene dichloride (2mL) for the 9-aminocarbamic acid tert-butyl ester.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)。

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

Under 0 ℃, (16 μ L 0.11mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (38mg, 0.11mmol) and the 4-chloroformate nitrophenyl ester (23mg is 0.11mmol) in the solution in tetrahydrofuran (THF) (2mL).After 1 hour, add 1-piperidin-4-yl imidazolidine-2, the 4-diketone (21mg, 0.11mmol) and triethylamine (47 μ L 0.33mmol), and are warming to room temperature with this mixture.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], obtain title compound (36mg).MS?555.2126(M+1)。

Substantially according to the preparation method of embodiment 113, prepare the embodiment compound in the table 13.

Table 13

Embodiment 120

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

Trifluoroacetic acid (2mL) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(50mg is 0.112mmol) in the solution in methylene dichloride (2mL) for the 9-aminocarbamic acid tert-butyl ester.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)。

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2-oxo-2,3- Dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-methane amide

Under 0 ℃, (24 μ L 0.174mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (30mg, 0.087mmol) and the 4-chloroformate nitrophenyl ester (18mg is 0.091mmol) in the solution in tetrahydrofuran (THF) (1mL).After 1 hour, add the 1H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-2 (3H)-ketone (21mg, 0.096mmol), (48 μ L 0.348mmol) and methylene dichloride (1mL), and are warming to room temperature with this mixture to triethylamine.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], obtain title compound (9.5 mg).MS?589.2369(M+1)。

Embodiment 121

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2,4-dioxo-1,3,8-three Azaspiro [4.5] decane-8-methane amide

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

Under 0 ℃, (12 μ L 0.087mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (30mg, 0.087mmol) and the 4-chloroformate nitrophenyl ester (18mg is 0.091mmol) in the solution in tetrahydrofuran (THF) (1mL).After 1 hour, add 1,3,8-thriazaspiro [4.5] decane-2, the 4-diketone (15mg, 0.091mmol), triethylamine (48 μ L, 0.348mmol) and N, dinethylformamide (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], obtain title compound (12mg).MS?541.1955(M+1)。

Embodiment 122

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

Trifluoroacetic acid (1mL) is added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(110mg is 0.57mmol) in the solution in methylene dichloride (2mL) for the 9-aminocarbamic acid tert-butyl ester.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,, filter and concentrate through dried over mgso.MS346.1(M+1)。

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

Under 0 ℃, (7.0 μ L 0.05mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (17mg, 0.05mmol) and the 4-chloroformate nitrophenyl ester (10.0mg is 0.05mmol) in the solution in tetrahydrofuran (THF) (3mL).After 20 minutes, add 3-piperidin-4-yl-1,3,4,5-tetrahydrochysene-2H-1, the 3-benzodiazepine _-the 2-keto hydrochloride (14mg, 0.05mmol) and triethylamine (21 μ L 0.15mmol), and are warming to room temperature with this mixture.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), obtain title compound (22mg).MS617.2609(M+1)。

Substantially according to the preparation method of embodiment 122, prepare the embodiment compound in the table 14.

Table 14

Embodiment 127

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

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

Under 0 ℃, (5.0 μ L 0.035mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (12.0mg, 0.035mmol) and the 4-chloroformate nitrophenyl ester (7.0mg is 0.035mmol) in the 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 are warming to room temperature with this mixture.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), obtain title compound (17mg).MS?600.2340(M+1)。

Substantially according to the preparation method of embodiment 127, prepare the embodiment compound in the table 15.

Table 15

Embodiment 132

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

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

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

Under 0 ℃, (37 μ L 0.50mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (70mg, 0.167mmol) and the 4-chloroformate nitrophenyl ester (34mg is 0.167mmol) in the solution in tetrahydrofuran (THF) (1mL).After 15 minutes, (30mg, (49 μ L 0.67mmol), and are warming to room temperature with this mixture for (1mL) solution of methylene dichloride 0.167mmol) and triethylamine to add 4-piperidin-4-yl pyridazine-3 (2H)-ketone.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), obtain title compound (51mg).MS?551.2152(M+1)。

Substantially according to the preparation method of embodiment 132, prepare the embodiment compound in the table 16.

Table 16

Embodiment 137

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1-oxo-2, the 8-diaza spiro [4.5] decane-8-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1-oxo-2,8- Diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, (32.2 μ L 0.23mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (32mg, 0.077mmol) and the 4-chloroformate nitrophenyl ester (15mg is 0.077mmol) in the solution in tetrahydrofuran (THF) (1mL).After 15 minutes, add 2, (15mg, (43 μ L 0.31mmol), and are warming to room temperature with this mixture to 8-diaza spiro [4.5] decane-1-ketone for (1mL) solution of methylene dichloride 0.077mmol) and triethylamine.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), obtain title compound (13mg).MS?526.2204(M+1)。

Substantially according to the preparation method of embodiment 137, prepare the embodiment compound in the table 17.

Table 17

Embodiment 140

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

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

Under 0 ℃, (33.0 μ L 0.24mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (33.0mg, 0.079mmol) and the 4-chloroformate nitrophenyl ester (16.0mg is 0.079mmol) in the solution in tetrahydrofuran (THF) (1mL).After 15 minutes, (15.0mg, (22 μ L 0.16mmol), and are warming to room temperature with this mixture for (1mL) solution of methylene dichloride 0.079mmol) and triethylamine to add 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone.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), obtain title compound (22mg).MS?565.2306(M+1)。

Substantially according to the preparation method of embodiment 140, prepare the embodiment compound in the table 18.

Table 18

Embodiment 144

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1,3-dioxo-2,8-phenodiazine Assorted spiral shell [4.5] decane-8-methane amide

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

Under 0 ℃, (0.28mL 1.97mmol) is added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (275mg, 0.66mmol) and the 4-chloroformate nitrophenyl ester (139mg is 0.69mmol) in the solution in tetrahydrofuran (THF) (2.5mL).After 15 minutes, add 2,8-diaza spiro [4.5] decane-1, (180mg, (0.28mL 1.97mmol), and is warming to room temperature with this mixture to the acetate of 3-diketone (WO 2004/076455) for (2.5mL) solution of methylene dichloride 0.79mmol) and triethylamine.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), obtain title compound (213mg).MS540.2005(M+1)。

Substantially according to the preparation method of embodiment 144, prepare the embodiment compound in the table 19.

Table 19

Embodiment 147

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

With trifluoroacetic acid (1mL, 13.5mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (120mg is in methylene dichloride 0.27mmol) (2mL) solution for t-butyl carbamate.After 1 hour, this mixture concentrates and the adding saturated sodium bicarbonate aqueous solution.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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1-methyl-2,4- Dioxo-1,3,8-thriazaspiro [4.5] decane-8-methane amide

Under 0 ℃, (70 μ L 0.50mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (70mg, 0.167mmol) and the 4-chloroformate nitrophenyl ester (34mg is 0.167mmol) in the solution in tetrahydrofuran (THF) (2mL).After 15 minutes, add the 1-methyl isophthalic acid, 3,8-thriazaspiro [4.5] decane-2, (31mg, (93 μ L 0.67mmol), and are warming to room temperature with this mixture to the 4-diketone for (2mL) solution of methylene dichloride 0.167mmol) and triethylamine.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), obtain title compound (33 mg).MS?555.2107(M+1)。

Embodiment 148

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-3-methyl-2-oxo-2,3 -dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-methane amide

With trifluoroacetic acid (1mL, 13.5mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-(120mg is 0.27mmol) in the solution in methylene dichloride (2mL) for the 9-aminocarbamic acid tert-butyl ester.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)。

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-3-methyl-2-oxygen Generation-2,3-dihydro-1H, 1 ' H-spiral shell [1,8-naphthyridines-4,4 '-piperidines]-1 '-methane amide

Under 0 ℃, (30 μ L 0.22mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (30mg, 0.07mmol) and the 4-chloroformate nitrophenyl ester (14mg is 0.07mmol) in tetrahydrofuran (THF) (1mL) solution.After 15 minutes, add 3-methyl isophthalic acid H-spiral shell [1,8-naphthyridines-4,4 '-piperidines] (17mg, (40 μ L 0.29mmol), and are warming to room temperature with this mixture to-2 (3H)-ketone for (1mL) solution of methylene dichloride 0.07mmol) and triethylamine.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), obtain title compound (10.9mg).MS?603.2451(M+1)。

Embodiment 149

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

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

Under 0 ℃, (33 μ L 0.24mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (33mg, 0.08mmol) and the 4-chloroformate nitrophenyl ester (16mg is 0.08mmol) in the solution in tetrahydrofuran (THF) (1mL).After 15 minutes, (20mg, (22 μ L 0.16mmol), and are warming to room temperature with this mixture for (1mL) solution of methylene dichloride 0.08mmol) and triethylamine to add 6-phenyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone.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), obtain title compound (22 mg).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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazoles And [1,2-a] azepine _-the 9-yl } piperidines-1-methane amide and N-{[6S, 9R)-6-(2,3- Difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2- A] azepine _-the 9-yl }-4-(3-oxo-6-propyl group-2,3-dihydrogen dazin-4-yl) Piperidines-1-methane amide

Step B:4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl)-N- [6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] azepine _-the 9-yl } piperidines-1-methane amide and N-{[6S, 9R) -6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl }-4-(3-oxo-6-propyl group-2, rattle away by the 3-dihydro Piperazine-4-yl) piperidines-1-methane amide

Under 0 ℃, (34 μ L 0.24mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (36mg, 0.081mmol) and the 4-chloroformate nitrophenyl ester (16mg is 0.081mmol) in the 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 are warming to room temperature with this mixture.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), obtain 4-(6-cyclopropyl-3-oxo-2,3-dihydrogen dazin-4-yl)-N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] piperidines-1-methane amide (11mg); MS 591.2507 (M+1) and N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 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

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

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

Under 0 ℃, (40 μ L 0.285mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (33mg, 0.095mmol) and the 4-chloroformate nitrophenyl ester (19mg is 0.095mmol) in the solution in methylene dichloride (2mL).After 15 minutes, (23mg, (26 μ L 0.19mmol), and are warming to room temperature with this mixture for (1mL) solution of methylene dichloride 0.105mmol) and triethylamine to add 3-piperidin-4-yl pyridine-2 (1H)-keto hydrochloride.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), obtain title compound (8.5mg).MS?650.2244(M+1)。

Embodiment 153

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-8,10-dioxo-3,9-two Azaspiro [5.5] hendecane-3-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-8, the 10-dioxo- 3,9-diaza spiro [5.5] hendecane-3-methane amide

Under 0 ℃, (30.3 μ L 0.215mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (30mg, 0.072mmol) and the 4-chloroformate nitrophenyl ester (15mg is 0.075mmol) in the solution in tetrahydrofuran (THF) (0.5mL).After 15 minutes, add 3,9-diaza spiro [5.5] hendecane-2, (19mg, (30.3 μ L 0.215mmol), and are warming to room temperature with this mixture to the acetate of 4-diketone for (1mL) solution of methylene dichloride 0.079mmol) and triethylamine.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), obtain title compound (17.4mg).MS?554.2196(M+1)。

Embodiment 154

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-oxo-1,3,8-three azepines Spiral shell [4.5] last of the ten Heavenly stems-1-alkene-8-methane amide

Hydrochloric acid (4.0M two _ alkane liquid; 4mL, 16.0rnmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (27mg is in two _ alkane 0.061mmol) (4mL) solution for t-butyl carbamate.After 18 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS346.2(M+1)。

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-oxo-1,3,8 -thriazaspiro [4.5] last of the ten Heavenly stems-1-alkene-8-methane amide

Under 0 ℃, (42 μ L 0.30mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (25mg, 0.061mmol) and the 4-chloroformate nitrophenyl ester (14mg is 0.070mmol) in the 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), (34 μ L 0.24mmol) and chloroform (5mL), and were warming to room temperature with this mixture to triethylamine.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), obtain title compound (22mg).MS?525.2000(M+1)。

Embodiment 155

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

Substantially according to preparing the method preparation that embodiment 10 compounds are summarized.MS590.2326(M+1)。

Embodiment 156

N-{ (6S, 9R)-6-(2, the 6-difluorophenyl)-3-ethyl-6,7,8,9-tetrahydrochysene-5H-miaow Azoles also [1,2-a] azepine _-the 9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Substantially according to preparing the method preparation that embodiment 10 compounds are summarized.MS536.2557(M+1)。

Embodiment 157

N-{ (6S, 9R)-6-(2, the 6-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 '-dihydro- The 1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-the 1-methane amide

Substantially according to preparing the method preparation that embodiment 47 compounds are summarized.MS575.2227(M+1)。

Embodiment 158

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

Steps A: (6S, 9R)-6-(2, the 6-difluorophenyl)-3-(1-methoxyl group-1-methyl second Base)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine

With sulfuric acid (0.15mL, 2.85mmol) be added to [(6S, 9R)-6-(2, the 6-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (120mg is in methyl alcohol 0.285mmol) (1.5mL) solution for t-butyl carbamate.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, the 6-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] _ piperazine]-the 1-methane amide

Under 0 ℃, with triethylamine (38 μ L, 0.27mmol) be added to (6S, 9R)-6-(2, the 6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine (95mg, 0.28mmol) and the 4-chloroformate nitrophenyl ester (60mg is 0.30mmol) in the solution in tetrahydrofuran (THF) (4mL).After 15 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 68mg, 0.31mmol) and triethylamine (120 μ L 0.85mmol), and are warming to room temperature with this mixture.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), obtain title compound (128mg).MS?581.2702(M+1)。

Substantially according to preparing the method that embodiment 158 is summarized, the embodiment compound in the preparation table 20.

Table 20

Embodiment 162

N-{ (6S, 9R)-6-(2, the 6-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl)-1-first The base ethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-1 '-first Base-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] _ piperazine] -1-methane amide

Steps A: 2-{1-[(6S, 9R)-9-amino-6-(2, the 6-difluorophenyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl]-the 1-methyl ethoxy } ethanol

With methylsulfonic acid (78 μ L, 1.19mmol) be added to [(6S, 9R)-6-(2, the 6-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (104mg is in ethylene glycol 0.24mmol) (4mL) solution for t-butyl carbamate.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, the 6-difluorophenyl)-3-[1-(2-hydroxyl-oxethyl) -1-methylethyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl } -1 '-methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3 -d] _ piperazine]-the 1-methane amide

Under 0 ℃, with triethylamine (53 μ L, 0.38mmol) be added to 2-{1-[(6S, 9R)-9-amino-6-(2, the 6-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 3-yl]-the 1-methyl ethoxy } ethanol (63mg, 0.17mmol) and the 4-chloroformate nitrophenyl ester (38mg is 0.19mmol) in the solution in tetrahydrofuran (THF) (10mL).After 20 minutes, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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), obtain title compound (64mg).MS?625.2989(M+1)。

Embodiment 163

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

Substantially according to preparing the method preparation that embodiment 120 is summarized.MS?589.2314(M+1)。

Embodiment 164

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

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

With hydrochloric acid (4.0M two _ alkane liquid; 5.0mL, 20.0mmol) be added to [(6S, 9R)-6-(2, the 6-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (265mg is in two _ alkane 0.60mmol) (5mL) solution for t-butyl carbamate.After 18 hours, this reaction mixture is concentrated, obtain the hydrochloride of title compound.MS?346.1(M+1)。

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

Under 0 ℃, (22 μ L 0.16mmol) are added to (6S with triethylamine, 9R)-6-(2, the 6-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (15mg, 0.04mmol) and the 4-chloroformate nitrophenyl ester (19mg is 0.043mmol) in the 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), obtain title compound (15mg).MS?565.2346(M+1)。

Embodiment 165

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

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

With hydrochloric acid (4.0M two _ alkane liquid; 3.0mL, 12.0mmol) be added to [(6S, 9R)-6-(2, the 6-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] (40mg is in two _ alkane 0.085mmol) (3mL) solution for t-butyl carbamate.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, the 6-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl }-4-(6-first Base-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Under 0 ℃, with triethylamine (55 μ L, 0.39mmol) be added to (6S, 9R)-6-(2, the 6-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-9-amine hydrochlorate (40mg, 0.10mmol) and the 4-chloroformate nitrophenyl ester (22mg is 0.11mmol) in the 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), obtain title compound (15mg).MS?591.2536(M+1)。

Embodiment 166

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

Substantially according to preparing the method preparation that embodiment 10 compounds are summarized.MS572.2377(M+1)。

Embodiment 167

N-{ (6S, 9R)-6-cyclohexyl-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H -imidazo [1,2-a] azepine _-the 9-yl }-4-(2-oxo-2,3-dihydro-1H-miaow Azoles is [4,5-b] pyridine-1-yl also) piperidines-1-methane amide

Substantially according to preparing the method preparation that embodiment 10 compounds are summarized.MS560.2974(M+1)。

Embodiment 168

N-{ (6S, 9R)-6-(2, the 3-dichlorophenyl)-3-ethyl-6,7,8,9-tetrahydrochysene-5H-miaow Azoles also [1,2-a] azepine _-the 9-yl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Substantially according to preparing the method preparation that embodiment 62 compounds are summarized.MS569.1784(M+1)。

Embodiment 169

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-miaow Azoles also [1,2-a] azepine _-the 9-yl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Steps A: [(3R, 6S)-2-cyano group-6-(2, the 3-difluorophenyl) azepine _-the 3-yl] amino T-butyl formate

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 is in tetrahydrofuran (THF) 2.95mmol) (5.0mL) solution.After 15 minutes, this mixture is warming to room temperature.After 3 hours, and adding 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, the 3-difluorophenyl) nitrogen heterocyclic Heptane-3-yl] t-butyl carbamate

Under 0 ℃, (1.29mL, (0.65g is in methylene dichloride 1.85mmol) (20mL) solution for t-butyl carbamate 9.25mmol) to be added to [(3R, 65)-2-cyano group-6-(2, the 3-difluorophenyl) azepan-3-yl] with triethylamine.(0.53mL 5.55mmol) also is warming to room temperature with this mixture to add diacetyl oxide.After 16 hours, add saturated sodium bicarbonate aqueous solution, and with this mixture dichloromethane extraction (3x).The organic extract liquid that merges filters and concentrates through the S-WAT drying.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-(hydrogen ylmethyl)-6-(2, the 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 to [(3R, 6S)-1-ethanoyl-2-cyano group-6-(2, the 3-difluorophenyl) azepan-3-yl] (80.0mg is in ethanol 0.20mmol) (10mL) solution for t-butyl carbamate.Fed 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, the 3-difluorophenyl)-3-methyl-5,6,7,8,9,9a-six hydrogen -1H-imidazo [1,5-a] azepine _-the 9-yl] t-butyl carbamate

Will [(3R, 6S)-1-ethanoyl-2-(amino methyl)-6-(2, the 3-difluorophenyl) azepan-3-yl] (22mg is in acetate 0.055mmol) (3mL) solution and be heated to 80 ℃ for t-butyl carbamate.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 filters and concentrates through the S-WAT drying.MS?380.1(M+1)。

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

Magnesium oxide (IV) (46.0mg, 0.53mmo]) is added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-methyl-5,6,7,8,9,9a-six hydrogen-1H-imidazo [1,5-a] azepine _-the 9-yl] (20.0mg is in toluene 0.053mmol) (7mL) solution for t-butyl carbamate.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, the 3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H -imidazo [1,5-a] azepine _-9-amine

With hydrochloric acid (4.0M two _ alkane liquid; 3.0mL, 12.0mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine _-the 9-yl] (33mg is in methylene dichloride 0.087mmol) (3mL) solution for t-butyl carbamate.After 2 hours, reaction mixture is concentrated, obtain the hydrochloride of title compound.MS278.1(M+1)。

Step G:N-{ (6S 9R)-6-(2, the 3-difluorophenyl)-3-methyl-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] nitrogen, assorted _-the 9-yl }-2 '-oxo-1 ', 2 '-dihydro-1H- Spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, with triethylamine (66 μ L, 0.476mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydrochysene-5H-imidazo [1,5-a] azepine _-9-amine hydrochlorate (30.0mg, 0.108mmol) and the 4-chloroformate nitrophenyl ester (31.0mg is 0.152mmol) in the solution in tetrahydrofuran (THF) (10mL).After 20 minutes, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (hydrochloride of 1 ' H)-ketone (and 95mg, 0.325mmol), 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 embodiment 169 compounds.MS581.2660(M+1)。

Embodiment 171

1-{ (6S, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrrole Pyridine is [2,3-d] [1,3] _ piperazine also]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2,3-two fluorobenzene Base)-and 3-(2,2, the 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] _ piperazine] 2 ' (1 ' H) -ketone

Steps A: (3S, 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2- Ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone

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, the 3-difluorophenyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) (634mg is 2.39mmol) in the suspension in toluene (50mL) for azepan-2-ketone.After 18 hours, 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, the 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, the 3-difluorophenyl) azepan-2-subunit] amino }-4,4, the 4-trifluoro Fourth-2-alcohol

Under 60 ℃, (96mg 0.36mmol) is added to (3S with mercury chloride (II), 6S)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone (100mg, 0.36mmol), 1-amino-4,4, the hydrochloride (167mg of 4-trifluoro fourth-2-alcohol, 0.93mmol) and triethylamine (150 μ L are 1.07mmol) in the solution in ethanol (2mL).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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoro Ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ and (6R, 9R)-9-alkene Propyl group-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8, the 9-tetrahydrochysene- 5H-imidazo [1,2-a] azepine _

Dichromic acid pyridine (296mg, 0.79mmo]) 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, the 3-difluorophenyl) azepan-2-subunit] amino }-4,4, (123g is 0.32mmol) in the solution in acetonitrile (10mL) for 4-trifluoro fourth-2-alcohol.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).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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9 -tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetate and (6R, 9R)-6-(2,3 -difluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2 -a] azepine _-the 9-yl] acetate

With sodium periodate (265mg, 1.24mmol) and potassium permanganate (22mg, 0.14mmol) be added to (6S, 9S)-9-allyl group-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ and (6R, 9R)-9-allyl group-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ (51mg is 0.14mmol) in the solution in tetrahydrofuran (THF) (3mL) and water (5mL).After 16 hours, add the saturated sodium sulfite aqueous solution and methylene dichloride, and transfer to pH4 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)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2,3 -difluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2 -a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]- 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetic acid hydrochloride and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetic acid hydrochloride (61mg, 0.144mmol), and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' ((38mg is 0.17mmol) in the solution in methylene dichloride (5mL) for 1 ' H)-ketone.After 18 hours, reaction mixture is heated to 45 ℃.1.5 after hour, 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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[6R, 9R)-6-(2,3 -difluorophenyl)-and 3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H- Imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3- D] [1,3] _ piperazine]-2 ' (1 ' H)-ketone

Step R:1-{[(2Z, 3S, 6S)-3-allyl group-6-(23-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, the 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, the 3-difluorophenyl) azepan-2-ketone and (3R, 6R)-3-allyl group-6-(2, the 3-difluorophenyl) azepan-2-ketone (100mg, 0.36mmol), (174mg is 1.31mmol) in the solution in ethanol (2mL) for 1-amino-3-methoxyl group-3-methyl fourth-2-alcohol.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, the 3-difluorophenyl)-3-(the 1-methoxyl group- The 1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ and (6R, 9R) -9-allyl group-6-(2, the 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 }-(155g is 0.41mmol) in the solution in acetonitrile (15mL) for 3-methoxyl group-3-methyl fourth-2-alcohol.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), obtain title compound (23mg).MS?361.2(M+1)。

Step D:[(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methyl second The base)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetate and (6R, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetate

With sodium periodate (123mg, 0.57mmol) and potassium permanganate (10mg, 0.064mmol) be added to (6S, 9S)-9-allyl group-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ and (6R, 9R)-9-allyl group-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _ (23mg is 0.064mmol) in the 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 pH4 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)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-first The base ethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } Spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R) -6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8, the 9-tetrahydrochysene -5H-imidazo [1,2-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone

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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetic acid hydrochloride and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-imidazo [1,2-a] azepine _-the 9-yl] acetic acid hydrochloride (26mg, 0.063mmol), and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' ((16mg is 0.075mmol) in the solution in methylene dichloride (3mL) for 1 ' H)-ketone.1.5 after hour, 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 (34 mg) of racemic mixture form.MS?580.2704(M+1)。

Embodiment 173

N-[(6S, 9S)-3-cyclopropyl-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H- [1,2,4] triazolo [4,3-a] azepine _-the 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, the 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) (502mg is in methyl alcohol 1.00mmol) (20mL) solution for piperidines-1-methane amide.After 30 minutes, reactant 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 the S-WAT drying, obtains title compound (515mg).MS?499.1(M+1)。

Step B:N-[(6S, 9S)-3-cyclopropyl-6-(2, the 3-difluorophenyl)-6,7,8,9-four Hydrogen-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-4-(2-oxo-2,3- Dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

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, reactant 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 the S-WAT drying.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 embodiment 173 compounds, prepare the embodiment compound in the table 21.

Table 21

Embodiment 180

N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-4-(2-oxo-2,3 -dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Steps A: (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine _-9-amine

With hydrochloric acid (4.0M two _ alkane liquid; 10mL, 40.1mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] t-butyl carbamate (618mg, 1.384mmol) 1, in 4-two _ alkane (5mL) solution.After 1 hour, reactant is concentrated, obtain the title compound (584mg) of dihydrochloride form.MS?347.1(M+1)。

Step B:N-[(6S9R)-6-(2 3-difluorophenyl)-3-(2 2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-4-(2-oxygen Generation-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide

Under 0 ℃, (58 μ L 0.417mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-9-amine dihydrochloride (50mg, 0.119mmol) and the 4-chloroformate nitrophenyl ester (25mg is in tetrahydrofuran (THF) 125mmol) (4mL) solution.After 15 minutes, add 2-oxo-1-piperidines _-4-base-2, (52mg, 0.179mmol), (58 μ L 0.417mmol) and methylene dichloride (3mL), are warming to room temperature with this mixture to triethylamine to 3-dihydro-1H-imidazo [4,5-b] pyridine-4-_ dichloride.After 5 hours, 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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-4-(3-first Base-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1 -methane amide

Steps A: (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-9-amine

Trifluoroacetic acid (7.5mL, 101.3mmol) tertiary butyl ((6S in the solution that is added to, 9R)-6-(2, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,839-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine _-the 9-yl } (0.38g is 0.80mmol) at methylene dichloride (15mL) for carbamate.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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-4- (3-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperazine Pyridine-1-methane amide

Under 0 ℃, with 1,1 '-carbonyl dimidazoles (24.0mg, 0.15mmol) be added to (6S, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-(28mg is in tetrahydrofuran (THF) 0.075mmol) (1.0mL) solution for 9-amine.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, and 3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones (23mg, 0.099mmol).After 1 hour, 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Steps A: (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-1- Methane amide

Under 0 ℃, (42 μ L 0.298mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 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 '-(29mg is 0.179mmol) in the solution in tetrahydrofuran (THF) (2mL) for carbonyl dimidazoles.After 1 hour, add spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (and 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 filters and concentrates through the S-WAT drying.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 embodiment 182 compounds, prepare the embodiment compound in the table 22.

Table 22

Embodiment 185

N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-1 '-methyl-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-1- Methane amide

Steps A: N-[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl]-1 '-methyl -2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ Piperazine]-the 1-methane amide

Under 0 ℃, (13 μ L 0.092mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-9-amine (32mg, 0.092mmol) and 1,1 '-(29mg is 0.179mmol) in the solution in tetrahydrofuran (THF) (1mL) for carbonyl dimidazoles.After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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 filters and concentrates through the S-WAT drying.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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 '-first Base-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3- D] [1,3] _ piperazine]-the 1-methane amide

Steps A: N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 ' -methyl-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3- D] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, (39 μ L 0.281mmol) are added to (6S with triethylamine, 9R)-and 6-(2, the 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 '-(32mg is 0.197mmol) in the solution in tetrahydrofuran (THF) (1mL) for carbonyl dimidazoles.After 1 hour, add 1 '-methylspiro [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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 filters and concentrates through the S-WAT drying.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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 '-(methoxymethyl) -2 '-hydrogen generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ Piperazine]-the 1-methane amide

Steps A: N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 '-(first The oxygen ylmethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3 -d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, (26 μ L 0.185mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (31mg of 9-amine, 0.074mmol) and 1,1 '-(21mg is in tetrahydrofuran (THF) 0.129mmol) (1mL) solution for carbonyl dimidazoles.After 1 hour, add 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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 filters and concentrates through the S-WAT drying.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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 '-(first The oxygen ylmethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3 -d] [1,3] _ piperazine]-the 1-methane amide

Steps A: N-{ (6S, 9)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 ' -(methoxymethyl)-2 '-oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-the 1-methane amide

Under 0 ℃, (39 μ L 0.281mmol) are added to (6S with triethylamine, 9R)-and 6-(2, the 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 '-(32mg is 0.197mmol) in the solution in tetrahydrofuran (THF) (1mL) for carbonyl dimidazoles.After 1 hour, add 1 '-(methoxymethyl) spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-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 filters and concentrates through the S-WAT drying.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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 '-oxo-1 ', 2 ' -dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] piperidines]-the 1-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] piperidines]-the 1-formyl Amine

Under 0 ℃, (52 μ L 0.370mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (62mg of 9-amine, 0.148mmol) and 1,1 '-(48mg is 0.296mmol) in the solution in tetrahydrofuran (THF) (5mL) for carbonyl dimidazoles.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, 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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 '-oxygen Generation-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-the 1-formyl Amine

Steps A: (6S, 9R)-6-(2, the 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 two _ alkane liquid; 10mL, 40.1mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] t-butyl carbamate (440mg, 0.93mmol) 1, in 4-two _ alkane (5mL) solution.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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-2 ' -oxo-1 ', 2 '-dihydro-1H-spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine]-1- Methane amide

Under 0 ℃, (39 μ L 0.28mmol) are added to (6S with triethylamine, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (50mg of 9-amine, 0.112mmol) and 1,1 '-(32mg is in tetrahydrofuran (THF) 0.197mmo1) (1.5mL) solution for carbonyl dimidazoles.After 30 minutes, add other 1,1 '-carbonyl dimidazoles (10mg, 0.062mmol).After 15 minutes, add 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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(2, the 4-dioxo Imidazolidine-1-yl) piperidines-1-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(2,4 -dioxo alkyl imidazole-1-yl) piperidines-1-methane amide

Under 0 ℃, (42 μ L 0.298mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (50mg of 9-amine, 0.119mmol) and 1,1 '-(44mg is 0.271mmol) in the solution in tetrahydrofuran (THF) (4mL) for carbonyl dimidazoles.After 1 hour, add 1-piperidin-4-yl imidazolidine-2, the 4-diketone (27mg, 0.149mmol) and methylene dichloride (3mL), and with this mixture heating up to 60 ℃.After 2 hours, 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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(the 2-oxo- 1,2-dihydroquinoline-3-yl) piperidines-1-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(2- Oxo-1,2-dihydroquinoline-3-yl) piperidines-1-methane amide

Under 0 ℃, (50 μ L 0.358mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (60mg of 9-amine, 0.143mmol) and 1,1 '-(41mg is 0.25mmol) in the solution in tetrahydrofuran (THF) (3mL) for carbonyl dimidazoles.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 (57.5 mg).MS?601.2312(M+1)。

Substantially according to the described method of preparation embodiment 192 compounds, prepare the embodiment compound in the table 23.

Table 23

Embodiment 196

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(the 2-oxo- 1,2,4,5-tetrahydrochysene-3H-1, the 3-benzodiazepine _-the 3-yl) piperidines-1-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(2- Oxo-1,2,4,5-tetrahydrochysene-3H-1, the 3-benzodiazepine _-the 3-yl) piperidines-1-first Acid amides

Under 0 ℃, (50 μ L 0.358mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (60mg of 9-amine, 0.143mmol) and 1,1 '-(41mg is 0.25mmol) in the solution in tetrahydrofuran (THF) (3mL) for carbonyl dimidazoles.After 25 minutes, add 3-piperidin-4-yl-1,3,4,5-tetrahydrochysene-2H-1, the 3-benzodiazepine _-hydrochloride of 2-ketone (40mg, 0.143mmol) 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 embodiment 196 compounds, prepare the embodiment compound in the table 24.

Table 24

Embodiment 200

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(3- Oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Step R:N-{ (6S9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl] -6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(3 -oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Under 0 ℃, (16 μ L 0.112mmol) are added to (6S with triethylamine, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (20mg of 9-amine, 0.045mmol) and 1,1 '-(13mg is in tetrahydrofuran (THF) 0.079mmol) (1.0mL) solution for carbonyl dimidazoles.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 embodiment 200 compounds, prepare the embodiment compound in the table 25.

Table 25

Embodiment 203

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

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(6- Methyl-3-oxo-2,3-dihydrogen dazin-4-yl) piperidines-1-methane amide

Under 0 ℃, (42 μ L 0.298mmol) are added to (6S to triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (50mg of 9-amine, 0.119mmol) and 1,1 '-(34mg is 0.209mmol) in the solution in tetrahydrofuran (THF) (2mL) for carbonyl dimidazoles.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 embodiment 203 compounds, prepare the embodiment compound in the table 26.

Table 26

Embodiment 206

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(the 2-oxo- 1,4-dihydroquinazoline-3 (2H)-yl) piperidines-1-methane amide

Step B:N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-4-(2- Oxo-1,4-dihydroquinazoline-3 (2h)-yl) piperidines-1-methane amide

Under 0 ℃, (50 μ L 0.356mmol) are added to (6S with triethylamine, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (60mg of 9-amine, 0.143mmol) and 1,1 '-(41mg is 0.25mmol) in the solution in tetrahydrofuran (THF) (3mL) for carbonyl dimidazoles.After 25 minutes, add 3-piperidin-4-yl-3, (38mg, 0.143mmol) and methylene dichloride (3mL), third with this mixture heating up to 60 ℃ for the hydrochloride of 4-dihydroquinazoline-2 (1H)-ketone.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

N-{ (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-the 1-oxo -2,8-diaza spiro [4.5] decane-8-methane amide

With hydrochloric acid (4.0M two _ alkane liquid; 5mL, 20.0mmol) be added to (6S, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl t-butyl carbamate (440mg, 0.93mmol) 1, in 4-two _ alkane (5mL) solution.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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 -oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Under 0 ℃, (16 μ L 0.112mmol) are added to (6S with triethylamine, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-dihydrochloride (20mg of 9-amine, 0.045mmol) and 1,1 '-(13mg is 0.079mmol) in the solution in tetrahydrofuran (THF) (1.0mL) for carbonyl dimidazoles.After 20 minutes, add other 1,1 '-carbonyl dimidazoles (7.3mg, 0.045mmol).After 30 minutes, add 2 again, the hydrochloride of 8-diaza spiro [4.5] decane-1-ketone (11mg, 0.056mmol) and methylene dichloride (1.0mL), and with this mixture heating up to 60 ℃.After 16 hours, 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, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl) ring third Base]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl }-1 -oxo-2,8-diaza spiro [4.5] decane-8-methane amide

Steps A: 2-[(6S, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8, the 9-tetrahydrochysene -5H-[1,2,4] triazolo [4,3-a] azepine _-the 3-yl] propan-2-ol

With hydrochloric acid (4.0M two _ alkane liquid; 5mL, 20.0mmol) be added to [(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(1-hydroxyl-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] t-butyl carbamate (176mg, 0.417mmol) 1, in 4-two _ alkane (5mL) solution.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, the 3-difluorophenyl)-3-(1-hydroxyl-1-methyl Ethyl) 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 ℃, (18 μ L 0.126mmol) are added to 2-[(6S with triethylamine, 9R)-9-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 3-yl] dihydrochloride (20mg of propan-2-ol, 0.051mmol) and 1,1 '-(14mg is 0.09mmol) in the solution in tetrahydrofuran (THF) (1.0mL) for carbonyl dimidazoles.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, 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8, the 9-tetrahydrochysene- 5H-[1,2,4] triazolo [4,3-a] azepine _-the 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 is added to 0.298mmol) that [6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (127mg of acetate, 0.298mmol) and 2-oxo-1-piperidines _-4-base-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-_ dichloride (87mg, 0.298mmol) at acetonitrile (3mL) and N, in the solution in the dinethylformamide (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 contains 0.1% trifluoroacetic acid) obtain racemic trans-compound 1-(1-{[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] ethanoyl piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-ones and 1-(1-{[(6R, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] ethanoyl piperidin-4-yl)-1,3-dihydro-2H-imidazo [4,5-d] pyridin-2-ones and 1-(1-{ ((6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9S)-(2,3-two for 6- Fluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetic acid hydrochloride (15.0mg, 0.035mmol) and 2 '-oxo-1 ', 2 '-the dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (13mg, 0.046mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,3 '-pyrrolo-[2,3-b] pyridine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-(2,3-two for 6- Fluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (15.0mg of acetate, 0.035mmol) and 2 '-oxo-1 ', 2 '-the dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (13mg, 0.046mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 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)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H -[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrroles And [2,3-b] pyridine]-2 ' (1 ' H)-ketone

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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (10.0mg of acetate, 0.024mmol) and 2 '-oxo-1 ', 2 '-the dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (8mg, 0.029mmol) at N, in the solution in the dinethylformamide (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 (9mg) of racemic mixture form.MS?565.2752(M+1)。

Embodiment 213

1-{[(6S, 9S)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 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)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H- [1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,3 '-pyrrolo- [2,3-b] pyridine]-2 ' (1 ' H)-ketone

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, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl hydrochloride of acetate and { (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 _-the 9-yl hydrochloride (15.0mg of acetate, 0.033mmol) and 2 '-oxo-1 ', 2 '-the dihydro spiral shell [piperidines-4,3 '-pyrrolo-[2,3-b] pyridine] dichloride (11mg, 0.040mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9S)-6-(2,3 -difluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-three Azoles also [4,3-a] azepine _-the 9-yl] ethanoyl spiral shell [piperidines-4,4 '-pyrido [2,3- D] [1,3] _ piperazine]-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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (15.0mg of acetate, 0.035mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (9mg, 0.042mmol) at N, in the solution in the dinethylformamide (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

1-{[(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines- 4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)-6-(2,3 -difluorophenyl)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-three Azoles also [4,3-a] azepine _-the 9-yl] ethanoyl spiral shell [piperidines-4,4 '-pyrido [2,3- D] [1,3] _ piperazine]-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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (15.0mg of acetate, 0.035mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (9mg, 0.042mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)- 6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8, the 9-tetrahydrochysene- 5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrrole Pyridine is [2,3-d] [1,3] _ piperazine also]-2 ' (1 ' H)-ketone

With triethylamine (41 μ L, 0.295mmol), (19.0mg is 0.101mmol) with the 1-hydroxyl-(11.0mg 0.084mmol) is added to [(6S to 7-azepine benzotriazole to N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride, 9S)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (35.0mg of acetate, 0.084mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (22.0mg, 0.101mmol) at N, in the solution in dinethylformamide (0.5mL) and the 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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-{[(6R, 9R)- 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H -[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } spiral shell [piperidines-4,4 '-pyridine And [2,3-d] [1,3] _ piperazine]-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, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl hydrochloride of acetate and { (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 _-the 9-yl hydrochloride (40.0mg of acetate, 0.089mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone (23.0mg, 0.106mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethyl } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-(2-{ (6R, 9R) -6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8, the 9-tetrahydrochysene- 5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethyl } spiral shell [piperidines-4,4 '-pyridine And [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone

Steps A: (6S, 9S)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl] -6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl)-the acetate first The base ester and (6R, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl] -6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl)-the acetate first The base ester

Under 0 ℃, with TMS two azomethanes (0.22mL, 0.438nunol) be 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 _-the 9-yl acetate hydrochloride and (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 _-the 9-yl (33mg is 0.073mmol) in the solution in methylene dichloride (3mL) and methyl alcohol (1mL) for the hydrochloride of acetate.After 30 minutes, 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, the 3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl] -6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl)-acetaldehyde and [6R, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl)-cyclopropyl]-6,7,8,9 -tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl)-acetaldehyde

Under-78 ℃, with diisobutyl aluminum chloride (1.0M hexane liquid; 0.25mL, 0.252mmol) be added to (6S, 9S)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl methyl acetate and { (6R, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl (18mg is 0.042mmol) in the solution in methylene dichloride (2mL) for methyl acetate.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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) ring Propyl group]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] second Base } spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone and 1-(2- (6R, 9R)-6-(2,3-two fluorine-based bases)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9- Tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethyl } spiral shell [piperidines-4,4 ' -pyrido [2,3-d] [1,3] _ piperazine]-2 ' (1 ' H)-ketone

With sodium cyanoborohydride (7.0mg, 0.111mmol) be 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 _-the 9-yl } acetaldehyde and { (6R, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-[α]] azepine _-the 9-yl } acetaldehyde (22.0mg, 0.055mmol) and spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] _ piperazine]-2 ' ((12.0mg is 0.055mmol) in the solution in methyl alcohol (3mL) for 1 ' H)-ketone.Reaction mixture transfers to pH3 with acetate.After 20 minutes, 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, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9 -tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperidines-4 -yl) pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9R)-6-(2, the 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) pyridazine-3 (2H)-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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate hydrochloride and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (15.0mg of acetate, 0.035mmol) and 4-piperidin-4-yl pyridazine-3 (2H)-ketone (8.0mg is 0.046mmol) at N, in the solution in the dinethylformamide (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 (15mg) of racemic mixture form.MS?551.2190(M+1)。

Embodiment 220

4-(1-{[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperazine Pyridine-4-yl) pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9S)-6-(2, the 3-difluorophenyl) -3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] Azepine _-the 9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate hydrochloride and [(6R, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride (15.0mg of acetate, 0.035mmol) and 4-piperidin-4-yl pyridazine-3 (2H)-ketone (8.0mg is 0.046mmol) at N, in the solution in the dinethylformamide (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 (16mg) of racemic mixture form.MS?551.2199(M+1)。

Embodiment 221

1-(1-{[(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9 -tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperidines-4 -yl) imidazolidine-2, and 4-diketone and 1-(1-{[(6R, 9R)-6-(2, the 3-difluorophenyl)-3 -(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] nitrogen Assorted _-the 9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2, the 4-diketone

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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate hydrochloride (15.0mg, 0.035mmol) and 1-piperidin-4-yl imidazolidine-2,4-diketone (10mg, 0.056mmol) at N, in the solution in the dinethylformamide (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 (16mg) of racemic mixture form.MS?555.2144(M+1)。

Embodiment 222

1-(1-{[(6S, 9R)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperazine Pyridine-4-yl) imidazolidine-2, and 4-diketone and 1-(1-{[(6R, 9S)-6-(2,3-two fluorobenzene Base)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3 -a] azepine _-the 9-yl] ethanoyl } piperidin-4-yl) imidazolidine-2, the 4-diketone

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, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9S)-6-(2, the 3-difluorophenyl)-3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetate hydrochloride (15.0mg, 0.035mmol) and 1-piperidin-4-yl imidazolidine-2,4-diketone (10mg, 0.053mmol) at N, in the solution in the dinethylformamide (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 (16mg) of racemic mixture form.MS?555.2161(M+1)。

Embodiment 223

3-[1-{[(6S, 9S)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperazine Pyridine-4-yl]-1,3,4,5-tetrahydrochysene-2H-1, the 3-benzodiazepine _-2-ketone and 3-[1 -[(6R, 9R)-6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperazine Pyridine-4-yl]-1,3,4,5-tetrahydrochysene-2H-1, the 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, the 3-difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl } hydrochloride of acetate and { (6R, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl } acetic acid hydrochloride (15.0mg, 0.033mmol) and 4-(2-oxo-1,2,4,5-tetrahydrochysene-3H-1, the 3-benzodiazepine _-the 3-yl) greening _ (11.0mg is 0.040mmol) at N, in the solution in the dinethylformamide (0.5mL) for piperidines.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, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl) -6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } Piperidin-4-yl) pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9R)-6-(2,3-two fluorobenzene Base)-and 3-(2,2, the 2-trifluoroethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3 -a] azepine _-the 9-yl] ethanoyl } piperidin-4-yl) pyridazine-3 (2H)-ketone

With triethylamine (3.0 μ L, 0.024mmol), (5.0mg is 0.024mmol) with 1-hydroxyl-7-azepine benzotriazole (3.0mg for N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride, 0.024mmol) be added to [(6S, 9S)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] hydrochloride of acetate and [(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(1-methoxyl group-1-methylethyl)-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl] acetic acid hydrochloride (10.0mg, 0.024mmol) and 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (6.0mg is 0.029mmol) at N, in the solution in the dinethylformamide (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, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]- 6,7,8,9-tetrahydrochysene-5H-[1,2,4]-triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperazine Pyridine-4-yl)-and 6-methyl pyridazine-3 (2H)-ketone and 4-(1-{[(6R, 9R)-6-(2,3- Difluorophenyl)-and 3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4]- Triazolo [4,3-a] azepine _-the 9-yl] ethanoyl } piperidin-4-yl)-6-methyl pyridazine- 3 (2H)-ketone

With triethylamine (43.0 μ L, 0.31mmol), (20.0mg is 0.106mmol) with 1-hydroxyl-7-azepine benzotriazole (12.0mg for N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride, 0.089mmol) be added to { (6S, 9S)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl } hydrochloride of acetate and { (6R, 9R)-and 6-(2, the 3-difluorophenyl)-3-[1-(trifluoromethyl) cyclopropyl]-6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-a] azepine _-the 9-yl } hydrochloride (40.0mg of acetate, 0.089mmol) and 6-methyl-4-piperidin-4-yl pyridazine-3 (2H)-ketone (21.0mg is 0.106mmol) at N, in the solution in the dinethylformamide (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 (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, under 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,, can use effective dose because Mammals is treated the reactions change of any indication to The compounds of this invention shown in using, but not the given dose that above provides.Equally, whether observed specific pharmacological reaction 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 the variation and the difference of this class expected results according to purpose of the present invention and practice.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:

With

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:

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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

R ²Be independently selected from:

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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

W is O, NR ⁴Or C (R ⁴) ₂

X is C or S;

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 ¹¹And

v)O(CO)R ⁴；

J is a key, C (R ⁶) ₂, O or NR 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 ⁴

R ^7aAnd R ^7bBe selected from R independently of one another 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.

2, formula Ia compound and pharmacologically acceptable salt thereof 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.

3, formula Ib compound and pharmacologically acceptable salt thereof and steric isomer monomer.

4, formula Ic compound and pharmacologically acceptable salt thereof and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

5, formula Id compound and pharmacologically acceptable salt thereof and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

6, formula Ie compound and pharmacologically acceptable salt thereof and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

7, formula If compound and pharmacologically acceptable salt thereof and steric isomer monomer:

Wherein:

A is C (R ²) ₂, O, S (O) _mOr NR ²

8, the compound of claim 1 and pharmacologically acceptable salt thereof and steric isomer monomer, wherein:

R1 is selected from:

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)CN，

L) NR ¹⁰R ¹¹And

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 ¹¹And

m)O(CO)R ⁴；

R ²Be selected from:

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)S(O) _mR ⁴，

l)CN，

M) NR ¹⁰R ¹¹And

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 ¹¹And

m)O(CO)R ⁴，

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 ¹¹And

M) O (CO) R ⁴And

Z be Z1 and:

J is a key, and V is a key, perhaps

J is a key, V be a key and T be-C (=O)-, perhaps

J is a key, 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), perhaps

J is a key, C (R ⁵) ₂, O or NR ⁵, V is a key, and perhaps Z is Z2, and G-L is selected from N, N-C (R ⁶) ₂, C=C (R ⁶), C=N and N-C (R ⁶) ₂-C (R ⁶) ₂

Q is 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 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)-；

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

M is 0-2;

S is 1-3.

9, the compound of claim 1 and pharmacologically acceptable salt thereof and steric isomer monomer, wherein R ¹Be selected from:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

D) heteroaryl, it is unsubstituted or is selected from R independently of one another by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: imidazoles, different _ azoles, _ azoles, pyrazine, give a tongue-lashing azoles, pyridazine, give a tongue-lashing pyridine, pyrimidine and thiazole;

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；

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 ¹¹And

m)O(CO)R ⁴；

R ²Be selected from:

A) C _1-6Alkyl,

B) C _3-6Cycloalkyl,

D) heteroaryl, it is unsubstituted or is selected from R independently of one another by 1-5 ⁴Substituting group replace, and wherein heteroaryl is selected from: benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, different _ azoles, _ azoles, give a tongue-lashing piperazine, pyrazoles, pyridazine, pyridine, pyrimidine, pyrroles, thiazole, thiophene and triazole;

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 ¹¹And

M) O (CO) R ⁴And

2) aryl or heteroaryl, they are selected from: phenyl, benzoglyoxaline, thionaphthene, furans, imidazoles, indoles, different _ azoles, _ azoles, give a tongue-lashing piperazine, pyrazoles, pyridazine, give a tongue-lashing pyridine, pyrimidine, pyrroles, thiazole, thiophene and triazole, 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 ¹¹And

m)O(CO)R ⁴，

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 ¹¹And

m)O(CO)R ⁴；

Z be Z1 and:

J is a key, and V is a key, and Q is-N (R ^7a)-, and T be-C (=O)-, perhaps

J is a key, and V is a key, and Q is-C (R ^7a) ₂-, and T be-C (=O)-, perhaps

J is a key, and V is a key, and Q is-N=, and T is=C (R ^7b)-, perhaps

J is a key, and V is a key, and Q is-C (R ^7a) ₂-, and T is-C (R ^7b) ₂-, perhaps

J is a key, and V is a key, 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, perhaps

J is a key, and V is C (R ⁶) ₂, 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, perhaps

J is O, and V is a key, 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;

Perhaps Z be Z2 and:

G-L is N, and Q is-C (R ^7a) ₂-, and T is-C (R ^7b) ₂-, perhaps

G-L is N, and Q is-C (R ^7a)=, and T are=C (R ^7b)-, perhaps

G-L is N, and Q is-N=, and T is=C (R ^7b)-, perhaps

G-L is N, and Q is-C (R ^7a) ₂-, and T be-C (O)-, perhaps

G-L is C=C (R ⁶), Q is-C (R ^7a)=and T be=C (R ^7b)-, perhaps

G-L is C=C (R ⁶), Q is-C (R ^7a)=and T be=N-, perhaps

G-L is C=C (R ⁶), Q is-N=and T be=C (R ^7b)-, perhaps

G-L is C=N, and Q is-C (R ^7a)=and T be=C (R ^7b)-, perhaps

G-L is N, 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, perhaps

G-L is N-C (R ⁶) ₂, 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, perhaps

G-J is C=N, 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, perhaps

G-L is C=C (R ⁶), 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, perhaps

G-L is N-C (R ⁶) ₂-C (R ⁶) ₂, 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;

R ^7aAnd R ^7bBe selected from R independently of one another 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.

10, formula II compound and pharmacologically acceptable salt thereof and diastereomer monomer:

Wherein:

B is (C (R ²) ₂) _n

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

R ¹Be independently selected from:

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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

R ²Be independently selected from:

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 ¹¹And

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 ¹¹And

v)O(CO)R ⁴；

W is O, NR ⁴Or C (R ⁴) ₂

X is C or S;

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 ₁₁And

v)O(CO)R ⁴；

J is a key, C (R ⁶) ₂, O or NR 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)-；

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.

11, a kind of compound and pharmacologically acceptable salt thereof and diastereomer monomer, it is selected from:

12, a kind of compound and pharmacologically acceptable salt thereof and diastereomer monomer, it is selected from:

13, a kind of pharmaceutical composition, it comprises the compound of inert support and claim 1.

14, the method for the mammiferous CGRP receptor active of a kind of antagonism comprises the compound of the claim 1 of using significant quantity.

15, a kind of treatment, control, the headache that improves or alleviate mammalian subject, migraine or neural partially headache or its dangerous method comprise the compound to the claim 1 of patient's administering therapeutic significant quantity of this treatment of need.

16, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from serotonin agonist, pain killer, antiphlogiston, antihypertensive drug and anticonvulsive drug with the treatment significant quantity.

17, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from antianxiety agent and psychosis with the treatment significant quantity.

18, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from beta-Blocking agent and calcium channel blocker with the treatment significant quantity.

19, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from thymoleptic, selective serotonin reuptake inhibitor and NE reuptake inhibitor with the treatment significant quantity.

20, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from botulinum toxin type A and botulinum toxin type B with the treatment significant quantity.

21, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Be selected from following medicine with second kind that treats significant quantity: anilloid receptor antagonist, adenosine 1 antagonist, NR2B antagonist, P substance antagonist, granzyme B inhibitor, endothelin antagonist, norepinephrine precursor, nitric oxide synthase inhibitor activity, psychosis, brad ykinin antagonists, gap are connected inhibitor, AMPA/KA antagonist, sigma-receptor agonist, chloride channel toughener, monoamine oxide inhibitor, opiates agonist and LTRA.

22, the method for a kind of treatment or prevention of migraine, neural partially headache and headache, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of the co-administered treatment significant quantity of the human patients of this treatment of need; Second kind of medicine that is selected from antiemetic, short motion agent and histamine H 1 antagonist with the treatment significant quantity.

23, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from serotonin agonist, pain killer, antiphlogiston and anticonvulsive drug with the treatment significant quantity.

24, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from Angiotensin II antagonist, angiotensin I antagonist, angiotensin-convertion enzyme inhibitor and renin inhibitor with the treatment significant quantity.

25, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from antianxiety agent and psychosis with the treatment significant quantity.

26, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from beta-Blocking agent and calcium channel blocker with the treatment significant quantity.

27, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from thymoleptic, selective serotonin reuptake inhibitor and NE reuptake inhibitor with the treatment significant quantity.

28, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from botulinum toxin type A and botulinum toxin type B with the treatment significant quantity.

29, a kind of pharmaceutical composition, it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; Be selected from following medicine with second kind that treats significant quantity: anilloid receptor antagonist, adenosine 1 antagonist, NR2B antagonist, P substance antagonist, granzyme B inhibitor, endothelin antagonist, norepinephrine precursor, nitric oxide synthase inhibitor activity, psychosis, brad ykinin antagonists, gap are connected inhibitor, AMPA/KA antagonist, sigma-receptor agonist, chloride channel toughener, monoamine oxide inhibitor, opiates agonist and LTRA.

30, a kind of pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity; The medicine that is selected from antiemetic, short motion agent and histamine H 1 antagonist with the treatment significant quantity.