CN117062607A

CN117062607A - Methyl substituted pyridine and pyridazine compounds, derivatives thereof and methods of use thereof

Info

Publication number: CN117062607A
Application number: CN202280020479.8A
Authority: CN
Inventors: 罗伯特·M·琼斯; 阿肖克·巴吉; 纳撒尼尔·J·T·蒙克; 苏珊娜·J·奥克尼; 理查德·E·拉特梅尔; 威廉·H·加德纳; 罗伯特·J·汤森德; 安德烈娜·P·皮塔; 麦可·布鲁纳维斯; 阿卜杜勒·卡达尔·谢赫; 强纳森·P·诗恩; 伊恩·J·威金顿; 强纳森·P·里查德; 马可·M·玛斯坦德里亚; 亚当·J·达文波特; 布莱恩·莫耶; 麦可·波斯尼; 詹姆士·巴罗
Original assignee: Laibai College Co ltd; Latiguo Biomedical Co ltd
Current assignee: Laibai College Co ltd; Latiguo Biomedical Co ltd
Priority date: 2021-03-11
Filing date: 2022-03-10
Publication date: 2023-11-14

Abstract

The present application provides methyl substituted pyridine and pyridazine compounds, derivatives thereof, and methods of use thereof. The compounds are useful as pharmacological agents for the treatment of a variety of conditions including various pain states, itching, and coughing.

Description

Methyl substituted pyridine and pyridazine compounds, derivatives thereof and methods of use thereof

Technical Field

The present application relates generally to methyl substituted pyridine and pyridazine compounds, derivatives thereof, and the use of such compounds as pharmacological agents.

Background

Millions of people suffer from conditions associated with pain, itching and/or coughing. In many cases, drugs used to treat such conditions fail to provide relief, or produce intolerable side effects. Thus, current treatments are inadequate for many patients suffering from various conditions.

Disclosure of Invention

The application provides a Na-type therapeutic and voltage-gated device _V 1.8 sodium channel associated with abnormal activity of conditions (such as pain, itching and cough).

A. A first group of compounds

In one aspect, the present application provides a compound of formula (I):

wherein:

R ₁ is-CN, -CF ₃ Optionally substituted 5 or 6 ring member rings including aryl or heteroaryl rings, wherein the 5 or 6 ring member rings optionally include one or more N or S in the ring, wherein the substitution on the 5 or 6 ring member rings is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, CF ₃ 、OCF ₃ A fused heterocyclyl group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group, or a partially unsaturated heterocyclyl group, each of which is optionally substituted as the valence permits;

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ halogen, alkyl or alkoxy;

R ₄ halogen, alkyl or H;

R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, CF ₃ 、OCF ₃ A fused heterocyclyl group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group, or a partially unsaturated heterocyclyl group, each of which is optionally substituted as the valence permits;

x is CH or N; and is also provided with

Z is CH or N, and the Z is CH or N,

with the proviso that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

R ₂ Can be-CH ₃ 、-CD ₃ or-CT ₃ Wherein D is deuterium and T is tritium.

R ₃ Can be-CH ₃ 、-CD ₃ or-CT ₃ Wherein D is deuterium and T is tritium.

R ₅ The moieties of (c) may be substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy or halogen.

The compounds of formula (I) may have a sulfonylimino group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In another aspect, the present invention provides a compound of formula (II):

wherein:

J ₁ 、J ₂ 、J ₄ and J ₅ Each of which is independently N, N-O or CR ₆ ；

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₆ each instance of (a) is independently H, halogen, C _1-3 Alkyl, C _3-5 Cycloalkyl, C _1-3 Alkoxy, CD ₃ Or CT ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ₇ Is H, halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ Heterocyclyl with 5 or 6 members per ring, withHeteroaryl, saturated heterocyclyl or partially unsaturated heterocyclyl of 5 or 6 ring members, O-aryl in which each ring has 5 or 6 members, O-heteroaryl, O-cycloalkyl, O-cycloheteroalkyl in which each ring has 5 or 6 members, each of which is optionally substituted where the valencies permit,

R ₈ H, C of a shape of H, C _1-3 Alkyl or C _3-5 Cycloalkyl groups, acyl groups, and the like,

the limiting conditions are as follows:

x and Z may not both be CH; and is also provided with

J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ Not more than two of them are N or N-O,

or a pharmaceutically acceptable salt thereof.

The compound of formula (II) may have a sulfonylimino group in R stereochemical configuration, S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In another aspect, the present invention provides a compound of formula (III):

wherein:

J ₃ For N, N-O or CR ₇ ；

W ₁ 、W ₂ 、W ₃ 、W ₄ And W is ₅ Each of which is independently N, CH or CR ₉ ；

X is CH or N;

z is CH, N or N-O,

R ₆ each instance of (C) is independently-H, halogen, C _1-3 Alkyl, C _3-5 Cycloalkyl, C _1-3 Alkoxy, CD ₃ Or CT ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ₇ is-H, halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ A carbocyclyl group in which each ring has 3 to 6 members, a heterocyclyl group in which each ring has 5 or 6 members, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group or a partially unsaturated heterocyclyl group in which each ring has 3 to 6 members, an O-aryl group in which each ring has 5 or 6 members, an O-heteroaryl group in which each ring has 5 or 6 members, an O-cycloalkyl group, an O-cycloheteroalkyl group, each of which is optionally substituted as the valence permits,

R ₉ Is independently-C (O) NR ₁₀ R ₁₁ 、-S(O) ₂ C _1-6 Alkyl, -S (O) (NH) C _1-6 Alkyl, C _1-3 Alkyl or C _3-5 Cycloalkyl; and is also provided with

R ₁₀ And R is ₁₁ Each of which is independently selected from-H and C _1-5 Alkyl, or R ₁₀ And R is ₁₁ Together with the nitrogen atom to which it is attached, form a heterocyclic group having 3 to 6 members, wherein the C _1-5 Each of the alkyl group and the heterocyclic group is optionally substituted as the valence permits,

the limiting conditions are as follows:

J ₁ 、J ₂ 、J ₃ 、J ₄ and J ₅ Not more than two of them are N or N-O;

W ₁ 、W ₂ 、W ₃ 、W ₄ and W is ₅ Not more than two of them are N;

W ₁ 、W ₂ 、W ₃ 、W ₄ and W is ₅ Not more than three of them are CR ₉ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

X and Z may not both be CH,

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a compound of formula (IV),

wherein:

y is N or CR ₁₃ ；

A and B are independently aryl, heteroaryl, or a 3-6 membered ring containing one or more heteroatoms independently selected from O, S and N; wherein a is unsubstituted or substituted with one or more substituents selected from the group consisting of:

H. halo, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR', -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH (CH) ₃ ) -cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH (-CH) ₃ ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH ₂ Hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR ' R "-NHSOR ', -NHC (=o) -alkyl-NH (c=o) NR ' R", SO ₂ R', trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sulfonylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

R ₁₂ 、R ₁₃ and R is ₁₄ Individually selected from: H. CF (compact flash) ₃ Halo, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH (CH) ₃ ) -cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH (-CH) ₃ ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH ₂ Hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR 'R' -NHSO ₂ R1, -NHC (=o) -alkyl-NH (c=o) NR' R ", spirocyclic-, morpholino-, pyrrolidino-, piperidinyl-, carbocyclyl-, heterocyclyl-, aryl-, or heteroaryl, wherein the 5 orThe 6 ring member ring optionally includes one or more N or S in the ring, wherein the substitution on the 5 or 6 ring member ring is selected from the group consisting of: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, -C (=o) -NH-alkyl, -C (=o) NH ₂ Cyano, CF ₃ 、CHF ₂ 、OCH ₃ 、OCF ₃ A fused heterocyclyl group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group, or a partially unsaturated heterocyclyl group, each of which is optionally substituted as the valence permits;

the substituents R 'and R' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted, unsubstituted heteroaryl, or CD ₃ 。

In selected embodiments, A is CH ₂ CF ₃ Or (b)

In another aspect, the present invention provides a compound of formula (V),

a and B are as described for formula (IV)

R ₂ As described for formula (II)

R ₁₃ And R is ₁₄ As described for formula (IV)

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O.

B. A second group of compounds

In one aspect, the present invention provides a compound of formula (I):

wherein:

R ₁ is-CN or-CF ₃ ；

R ₃ Is halogen, alkyl, alkoxy or-CD ₃ ；

E is CH or CF;

x is CH or N;

z is CH or N; and is also provided with

-CD ₃ In order to have a completely deuterated methyl group,

with the proviso that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

C. A third group of compounds

In one aspect, the present invention provides a compound of formula (I):

wherein:

R ₁ is halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl, haloalkyl, halocycloalkyl or H;

R ₂ selected from the group consisting of aryl,Heteroaryl and unsaturated heterocyclyl, wherein:

each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally fused to one selected from the group consisting of: an optionally saturated carbocyclyl group containing 5 to 6 ring members and an optionally saturated heterocyclyl group containing 5 to 6 ring members and 1 to 3 heteroatoms;

each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: - (CH) ₂ ) _n NR ^e C(O)N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e C(O)NR ^e R ^j 、-(CH ₂ ) _n NR ^e C(O)OR ^j 、-(CH ₂ ) _n NR ^e C(O)R ^j 、-(CH ₂ ) _n NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m R ^j Alkyl iminothiolonyl, alkyl sulfinyl, alkyl sulfonamide, alkyl sulfonyl, alkyl sulfoxide, alkyl sulfonimide, alkyl sulfide, amino, aryl, arylalkoxy, aryloxy, -C (O) NH ₂ 、-C(O)NR ^e R ^j 、-C(O)R ^j 、C ₁ -C ₄ Alkoxy, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ Cycloalkyl, -CF ₃ 、-CN、-CO ₂ H、-CO ₂ R ^j Cyano, -H, halogen, heteroaryl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihaloalkoxy, morpholino, nitro, O-aryl、-OC(O)N(R ^j ) ₂ 、-OC(O)NR ^e R ^j 、-OC(O)R ^j 、-OC ₁ -C ₆ Alkyl, -OC ₂ -C ₆ Alkenyl, -OC ₂ -C ₆ Cycloheteroalkyl, -OC ₃ -C ₆ Cycloalkyl, -OH, O-heteroaryl, oxazolyl, oxo, -S (O) ₂ R ^j 、-SO ₂ Aryl, -SO ₂ C ₁ -C ₆ Alkenyl, -SO ₂ C ₁ -C ₆ Alkyl, -SO ₂ C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ C ₃ -C ₆ Cycloalkyl, SO ₂ Heteroaryl, -SO ₂ NH ₂ 、-SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C ₂ -C ₆ Alkenyl, -SO ₂ NR ^e C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H、-SR ^j Sulphoxide imino-S (O) (=nr ^a )R ^a sulfonylamidine-S (O) (=nr ^a )N(R ^a ) ₂ Sulfonimidyl fluoride-S (O) (=nr ^a ) F and sulfonyldiimine-S (=nr ^a ) ₂ R ^a Wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl) and-N (C) ₁ -C ₆ Alkyl group ₂ ；

The unsaturated heterocyclic group is optionally substituted with R ^k R ^l Substitution; and is also provided with

Each heteroatom in the heteroaryl, unsaturated heterocyclyl and optionally saturated heterocyclyl is independently O, S or N (R ^h ) _q Each of which is provided withMay be in its oxidized or unoxidized state;

R ₃ selected from the group consisting of: -H, cyano, halogen, C ₁ -C ₄ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, optionally substituted C ₁ -C ₈ Alkyl and C optionally substituted with 1-4 fluorine atoms ₃ -C ₈ Cycloalkyl;

each R ^a Independently is halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₄ Cycloalkyl, haloalkyl, halocycloalkyl or H;

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

each R ^j Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, C ₂ -C ₆ Cycloheteroalkyl, aryl or heteroaryl, wherein R is ^j Optionally substituted with one or more substituents independently selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, -OH, -OC ₁ -C ₆ Alkyl, -OC ₃ -C ₆ Cycloalkyl, halogen, cyano and-S (O) ₂ CH ₃ ；

R ^k And R is ^l Together with the atoms to which they are attached form cycloalkyl or cycloheteroalkyl groups containing 3 to 7 ring members;

e is CH, CF or N;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N orN ⁺ O ^- ；

Z is N or N ⁺ O ^- Or CH;

each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

R ₂ May be an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted unsaturated heterocyclyl.

R ₁ Can be H, halogen or C ₁ -C ₃ Alkyl, C ₃ -C ₄ Cycloalkyl, haloalkyl or halocycloalkyl.

R ₃ Can be monohalogenated, dihalo or trihalogenated C ₁ -C ₄ An alkyl group. R is R ₃ Can be-CF ₃ 。

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

D. A fourth group of compounds

In one aspect, the present invention provides a compound of formula (I):

wherein:

R ₁ is halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₄ Cycloalkyl, haloalkyl, halocycloalkyl or H;

R ₂ selected from the group consisting of aryl, heteroaryl, and unsaturated heterocyclyl, wherein:

each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: - (CH) ₂ ) _n NR ^e C(O)N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e C(O)NR ^e R ^j 、-(CH ₂ ) _n NR ^e C(O)OR ^j 、-(CH ₂ ) _n NR ^e C(O)R ^j 、-(CH ₂ ) _n NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m R ^j Alkyl iminothiolonyl, alkyl sulfinyl, alkyl sulfonamide, alkyl sulfonyl, alkyl sulfoxide, alkyl sulfonimide, alkyl sulfide, amino, aryl, arylalkoxy, aryloxy, -C (O) NH ₂ 、-C(O)NR ^e R ^j 、-C(O)R ^j 、C ₁ -C ₄ Alkoxy, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ Cycloalkyl, -CF ₃ 、-CN、-CO ₂ H、-CO ₂ R ^j Cyano, -H, halogen, heteroaryl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihaloalkoxy, morpholino, nitro, O-aryl, -OC (O) N (R) ^j ) ₂ 、-OC(O)NR ^e R ^j 、-OC(O)R ^j 、-OC ₁ -C ₆ Alkyl, -OC ₂ -C ₆ Alkenyl, -OC ₂ -C ₆ Cycloheteroalkyl, -OC ₃ -C ₆ Cycloalkyl, -OH, O-heteroaryl, oxazolyl, oxo, -S (O) ₂ R ^j 、-SO ₂ Aryl, -SO ₂ C ₁ -C ₆ Alkenyl, -SO ₂ C ₁ -C ₆ Alkyl, -SO ₂ C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ C ₃ -C ₆ Cycloalkyl, SO ₂ Heteroaryl, -SO ₂ NH ₂ 、-SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C ₂ -C ₆ Alkenyl, -SO ₂ NR ^e C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H、-SR ^j Sulphoxide imino-S (O) (=nr ^a )R ^a sulfonylamidine-S (O) (=nr ^a )N(R ^a ) ₂ Sulfonimidyl fluoride-S (O) (=nr ^a ) F and sulfonyldiimine-S (=nr ^a ) ₂ R ^a Wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl) and-N (C) ₁ -C ₆ Alkyl group ₂ ；

Each heteroatom in the heteroaryl, unsaturated heterocyclyl and optionally saturated heterocyclyl is independently O, S or N (R ^h ) _q Each of which may be in its oxidized or unoxidized state;

R ₃ selected from the group consisting of: -H, cyano, halogen, C ₁ -C ₄ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, optionallySubstituted C ₁ -C ₈ Alkyl and C optionally substituted with 1-4 fluorine atoms ₃ -C ₈ Cycloalkyl;

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

E is CH or CF;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N or N ⁺ O ^- ，

Each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

E. A fifth group of compounds

In some aspects, the presently disclosed subject matter provides a compound of formula (I):

wherein:

R ₁ is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted with one or more groups selected from the group consisting of: mono-, di-and tri-halogenated C ₁ -C ₄ Alkyl, substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₁₀ Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C ₁ -C ₈ Alkoxy, monohalo, dihalo or trihaloalkoxy, thio, trifluoromethylthio and arylalkoxy;

R ₂ Selected from the group consisting of: aryl, heteroaryl, and heterocycle, wherein the aryl, heteroaryl, and heterocycle are unsubstituted or substituted with one or more groups selected from the group consisting of: mono-, di-and tri-halogenated C ₁ -C ₄ Alkyl, substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₁₀ Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C ₁ -C ₈ Alkoxy, monohalo, dihalo or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminothioonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

R ₃ selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, -NO ₂ ；

R ₄ Selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, substituted or unsubstituted C ₁ -C ₈ Alkyl and morpholinyl, provided that R ₃ And R is ₄ Are not hydrogen at the same time; or (b)

R ₃ And R is R ₄ Together form a mixture comprising R ₃ And R is R ₄ C of attached carbon atoms ₃ -C ₅ A carbocycle; and pharmaceutically acceptable salts thereof.

In some aspects of the compounds of formula (I), R ₁ Is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with one or more groups selected from the group consisting of: substituted or unsubstituted C ₁ -C ₈ An alkyl group; halogen; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1,2,3, 4, 5, 6, 7 and 8; -S-CF ₃ ；

R ₂ Selected from the group consisting of: phenyl group,Pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of: unsubstituted or substituted C ₁ -C ₈ An alkyl group; halogen; cyano group; an oxo group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ and-CHF ₂ A group of groups; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1,2,3, 4, 5, 6, 7 and 8; -NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; morpholinyl; oxazolyl; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl and R ₁₁ Is C ₁ -C ₄ Alkyl, provided that when Y is nitrogen and R ₂ R in the case of phenyl or pyridyl ₈ Not being-NR ₆ R ₇ ；

R ₃ Selected from the group consisting of: hydrogen, cyano, halogen, -CF ₃ 、C ₁ -C ₈ Alkoxy, -O-CH (F) ₂ Substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, -N ⁺ (＝O)-O ^- ；

R ₄ Selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, -CF ₃ Substituted or unsubstituted C ₁ -C ₈ Alkyl and morpholinyl, provided that R ₃ And R is ₄ Are not hydrogen at the same time; or (b)

R ₃ And R is R ₄ Together form a mixture comprising R ₃ And R is R ₄ C of attached carbon atoms ₃ -C ₅ Carbocycles.

In certain aspects, the compound of formula (I) comprises a compound of formula (II):

wherein:

R ₄ Selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, monohalo, dihalo and trihaloC ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, substituted or unsubstituted C ₁ -C ₈ Alkyl and morpholinyl, provided that R ₃ And R is ₄ Are not hydrogen at the same time; or (b)

R ₃ And R is R ₄ Together form a mixture comprising R ₃ And R is R ₄ C of attached carbon atoms ₃ -C ₅ A carbocycle;

n is an integer selected from 0, 1, 2, 3, 4 and 5;

each R ₂₄ Independently selected from the group consisting of: mono-, di-and tri-halogenated C ₁ -C ₄ Alkyl, substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₁₀ Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C ₁ -C ₈ Alkoxy, monohalo, dihalo or trihaloalkoxy, thio, trifluoromethylthio and arylalkoxy.

In some aspects of the compounds of formula (II), R ₂ Selected from the group consisting of:

wherein:

m is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

R ₂₅ selected from the group consisting of: h is formed; morpholinyl; oxazolyl; halogen; cyano group; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl and R ₁₁ Is C ₁ -C ₄ Alkyl, provided that when Y is nitrogen and R ₂ R in the case of phenyl or pyridyl ₈ Not being-NR ₆ R ₇ ；

R ₂₆ Halogen or cyano;

each R ₂₇ Independently selected from the group consisting of: H. halogen, C ₁ -C ₈ Alkoxy, cyano and-NR ₆ R ₇ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Each R ₂₈ Independently H or C ₁ -C ₄ An alkyl group.

In some aspects, the compound of formula (I) comprises a compound of formula (III):

wherein:

R ₁ selected from the group consisting of phenyl, pyridinyl, and 1, 3-benzothiazol-4-yl, wherein the phenyl and pyridinyl may be unsubstituted or substituted with one or more of: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups;

R ₂ selected from the group consisting of:

and is also provided with

R ₃ And R is ₄ Is H or-CF ₃ With the proviso that if R ₃ Is H, then R ₄ is-CF ₃ And if R ₄ Is H, then R ₃ is-CF ₃ 。

In some aspects, the compound of formula (I) comprises a compound of formula (IV):

wherein R is ₂ Selected from the group consisting of:

(i)wherein R is _2b Selected from the group consisting of H, C ₁ -C ₄ Alkyl and halogen; and R is ₁₄ Is C ₁ -C ₄ An alkyl group;

(ii)wherein R is _5b Selected from the group consisting of: -C (=o) -R ₈ 、-(CH ₂ ) _n OH and cyano, wherein R ₈ Is C ₁ -C ₄ Alkyl and n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8;

(iii)wherein R is _5b' Selected from H, halogen and C ₁ -C ₄ Alkyl groups;

(iv)wherein R is _4b Is H or halogen;

(v)wherein R is ₉ Is H or C ₁ -C ₄ An alkyl group; and->

(vi)

F. Methods of using compounds

In another aspect, the present invention provides Na _V Inhibitors of sodium channels 1.8. Inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above.

In another aspect, the invention provides a method of treating a condition in a subject by providing a compound of the invention (e.g., any of those described above) to the subject suffering from the condition.

The condition can be combined with Na _V 1.8 abnormal activity of sodium channels is correlated. The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itching, acute pain from severe trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, idiopathic reactions, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn, oral burning syndrome, calcium pyrophosphate deposition disease, cervicales-derived headache, charcol's neuro-osteoarthropathy (Charcot neuropathic osteoarthropathy), chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic low back pain, chronic pancreatitis chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, sustained unilateral facial pain with additional episodes, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic hyperosteogeny, intervertebral disc degenerative pain, distal Sensory Polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), eiles-Danlos syndrome (ehles-Danlos syndrome), endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, fabry's disease, facet joint syndrome, lumbar hand pain Operative failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, limb bone striated hypertrophy, migraine, multiple sclerosis, musculoskeletal injury, myofascial oral facial pain, post-ischemic neurodegeneration, type II neurofibroma, neuropathic eye pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, oral facial pain, osteoarthritis, overactive bladder, congenital thick nail syndrome, pain resulting from cancer, pain resulting from chemotherapy, and pain arising from diabetes, pain syndrome, painful arthroplasty, pancreatitis, parkinson's disease, paroxysmal extreme pain, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, post-operative pain, post-stroke pain, post-operative pain, postthoracic pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritis, psoriasis, psoriatic arthritis, pudendum neuralgia, pyoderma gangrene, radiation therapy-induced peripheral neuropathy, raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, idiopathic pain, stump pain, subacute cough, temporomandibular joint disease, tension headache, trigeminal neuralgia, vascular leg ulcers, vulvar pain, and cervical whiplash. In another aspect, the invention provides methods of using the compounds of the invention (e.g., any of those described above) to prepare medicaments.

In another aspect, the invention provides a product comprising a compound of the invention (e.g., any of those described above) for use in treating a condition (e.g., any of those described above) in a subject.

Drawings

Fig. 1: description for carrying out Na _v 1.8 inhibition assay protocol 1.

Detailed Description

A. Definition of the definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs. The definitions provided below are intended to complement and not exclude definitions that will be apparent to one of ordinary skill in the art after reviewing this disclosure.

Unless otherwise indicated, the moieties described below are optionally substituted, i.e., they may be substituted at one or more positions. As used herein, the terms substituted and substituent, whether preceded by the term "optionally" or not, refer to the ability to alter one or more functional groups on a molecule with the proviso that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. The substituents may be further substituted (e.g., one aryl substituent may have another substituent leaving it, e.g., another aryl group, further substituted at one or more positions).

When the term "independently selected" is used, the substituents referred to (e.g., R groups, e.g., group R ^h 、R ^j Etc., or variables such as "m" and "n") may be the same or different. For example, R ^h And R is ^j All can be substituted alkyl, or R ^h Can be hydrogen and R ^j May be a substituted alkyl group, etc.

The term "a/an/a (n))" when used in reference to a set of substituents herein means at least one. For example, when a compound is substituted with "one" alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl. Further, where a moiety is substituted with an R substituent, the group may be referred to as "substituted with R". In the case of a moiety substituted with R, the moiety is substituted with at least one R substituent and each R substituent is optionally different.

Unless otherwise specified herein, a named "R" or group will generally have a structure recognized in the art as corresponding to the group having that name. For purposes of illustration, certain representative "R" groups are defined as set forth below.

The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted with one or more of a plurality of substituents, such substitution is selected so as to conform to the principle of chemical bonding and result in a compound that is itself unstable and/or that is known by one of ordinary skill in the art to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom according to chemical bonding principles known to those skilled in the art, thereby avoiding inherently unstable compounds.

As used herein, unless explicitly defined otherwise, "substituent" includes a functional group selected from one or more of the following moieties, which are defined herein.

As used herein, the term hydrocarbon refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As known to those skilled in the art, all valences must be satisfied when any substitution is made. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, t-butyl, ethynyl, cyclohexyl, and the like.

Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight (i.e., unbranched) or branched, acyclic, or cyclic saturated hydrocarbon group, or a combination thereof, and may include divalent and multivalent groups having the indicated number of carbon atoms (e.g., C _1-10 Meaning one to ten carbonsIncluding 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term "alkyl" refers to C _1-10 (inclusive), including straight (i.e., "straight-chain"), branched or cyclic saturated hydrocarbon groups of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon atoms, obtained by removing a single hydrogen atom from a hydrocarbon group containing from one to twenty carbon atoms.

Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs and isomers thereof.

"branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a straight alkyl chain. "lower alkyl" means having from 1 to about 8 carbon atoms (i.e., C _1-8 Alkyl), for example alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. "higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

The alkyl group may be optionally substituted with one or more alkyl substituents, which may be the same or different ("substituted alkyl"). The term "alkyl substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxy, aryloxy, alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can optionally be inserted along the alkyl chain, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

Thus, as defined herein, the term "substituted alkyl" includes alkyl groups in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain hydrocarbon radical having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon radical having from 3 to 15 carbon atoms or heteroatoms or a combination thereof, consisting of at least one carbon atom and at least one heteroatom (e.g., O, N, P, si or S), and wherein the nitrogen, phosphorus and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, P, S and Si may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH ₂ -CH ₂ -O-CH ₃ 、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ 、-CH ₂ -S-CH ₂ -CH ₃ 、-CH ₂ -CH ₂ -S(O)-CH ₃ 、-CH ₂ -CH ₂ -S(O) ₂ -CH ₃ 、-CH＝CH-O-CH ₃ 、-Si(CH ₃ ) ₃ 、-CH ₂ -CH＝N-OCH ₃ 、-CH＝CH-N(CH ₃ )-CH ₃ 、O-CH ₃ 、-O-CH ₂ -CH ₃ and-CN. Up to two or three heteroatoms may be consecutive, e.g. -CH2-NH-OCH ₃ and-CH ₂ -O-Si(CH ₃ ) ₃ 。

As described above, heteroalkyl groups, as used herein, include those groups that are linked to the remainder of the molecule through a heteroatom, such as-C (O) NR ', -NR' R ', -OR', -SR, -S (O) R, and/OR-S (O) ₂ )R'。

"cycloalkyl" refers to a saturated monocyclic or multicyclic ring system of about 3 to about 15 carbon atoms, for example 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Cycloalkyl groups may also be optionally substituted with alkyl substituents, oxo groups and/or alkylene groups as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can optionally be inserted along the cyclic alkyl chain wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.

The term "cycloalkylalkyl" as used herein refers to cycloalkyl as defined above, which is substituted with an alkylene moiety (also defined above, e.g., C _1-20 An alkylene moiety) is attached to the parent molecular moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

The term "carbocyclyl" refers to a monocyclic or multicyclic ring system having about 3 to about 15 ring members, wherein all ring members are carbon atoms. Unless otherwise specified, carbocyclyl groups may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic.

The term "heterocyclyl" refers to a monocyclic or multicyclic ring system of about 3 to about 15 ring members, at least one of which is a heteroatom, e.g., N, O or S. Unless otherwise specified, a heterocyclyl group may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non-aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1, 3-oxacyclohexenyl, 1, 3-thiazinidinyl, 4,5, 6-tetrahydropyrimidinyl, 2, 3-dihydrofuryl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiazolyl, triazolyl, azabicyclo-octyl, diazabicyclo-octyl, and all alkyl-, alkoxy-, haloalkyl-and haloalkoxy-substituted derivatives of any of the foregoing.

The terms "cycloheteroalkyl" and "heterocycloalkyl" refer to saturated ring systems, such as 3-to 10-membered cycloalkyl ring systems, which include one or more heteroatoms. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O) or sulfur (S). Examples of heterocycloalkyl groups include, but are not limited to, 1- (1, 2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The cycloheteroalkyl ring may optionally be fused or otherwise connected to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Heterocycles include those having one to three heteroatoms (e.g., oxygen, sulfur, and nitrogen), where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, bicyclic or tricyclic groups comprising a fused six-membered ring having one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatoms may optionally be quaternized, and (iv) any of the above heterocycles may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazolinyl, tetrahydrofuranyl, and the like.

Unsaturated hydrocarbons, carbocyclyl or heterocyclyl groups have one or more double or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher homologs and isomers.

The term "alkenyl" as used herein refers to a group derived from a C having at least one carbon-carbon double bond by removal of a single hydrogen molecule _2-20 (inclusive) monovalent groups derived from straight or branched hydrocarbon moieties. Alkenyl groups include, for example, vinyl (i.e., ethenyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenylAlkenyl, allenyl and butadienyl.

The term "cycloalkenyl" as used herein refers to cyclic hydrocarbons containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1, 3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

As used herein, the term "alkynyl" refers to a straight or branched chain C derived from a carbon-carbon triple bond containing at least one designed number of carbon atoms _2-20 Monovalent groups of hydrocarbons. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, heptynyl and the like.

The term "alkylene" by itself or as part of another substituent refers to a straight or branched chain divalent aliphatic hydrocarbon radical derived from an alkyl radical having from 1 to about 20 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The alkylene group may be straight, branched or cyclic. The alkylene groups may also be optionally unsaturated and/or substituted with one or more "alkyl substituents". One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") may optionally be inserted along the alkylene group, wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH) ₂ (-) -; ethylene (-CH) ₂ -CH ₂ (-) -; propylene (CH) ₂ ) ₃ The method comprises the steps of carrying out a first treatment on the surface of the Cyclohexylidene (-C) ₆ H ₁₀ -)；-CH＝CH-CH＝CH-；-CH＝CH-CH ₂ -；-CH ₂ CH ₂ CH ₂ CH ₂ -；-CH ₂ CH ₂ CH(CH ₂ CH ₂ CH ₃ )CH ₂ -；-(CH ₂ ) _q -N(R)-(CH ₂ ) _r -, wherein each of q and R is independently an integer from 0 to about 20, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxy (-O-CH) ₂ -O-); and ethylenedioxy (-O- (CH) ₂ ) ₂ -O-)。

The term "heteroalkylene" by itself or as part of another substituent means a divalent group derived from a heteroalkyl, as exemplified by, but not limited to: -CH ₂ -CH ₂ -S-CH ₂ -CH ₂ -and-CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -. For heteroalkylene groups, the heteroatom can also occupy two or either chain end (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, the direction in which the linker chemical formula is written does not imply a linker orientation for the alkylene and heteroalkylene linkers. For example, the formula-C (O) OR ' -represents both-C (O) OR ' -and-R ' OC (O) -.

The term "spirocyclic group" refers to a polycyclic compound wherein both rings have a single atom (e.g., carbon) as the only common member of both rings. Thus, "spirocycloalkyl" refers to cycloalkyl groups having two rings that share a single carbon, and "spiroheterocycloalkyl" or "spiroheterocycloalkyl" refers to cycloheteroalkyl groups having two rings that share a single carbon or other atom (e.g., nitrogen).

Unless otherwise indicated, the term "aryl" means an aromatic hydrocarbon substituent that may be a single ring or multiple rings (e.g., 1 to 3 rings) that are fused together or covalently linked.

The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms (in each individual ring in the case of multiple rings) selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups may be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. The substituents of each of the above mentioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

Where a heteroalkyl, heterocycloalkyl, or heteroaryl group includes a particular number of members (e.g., "3-7 membered"), the term "membered" refers to a carbon atom or heteroatom.

Each of the above terms is intended to include both substituted and unsubstituted forms of the specified group. The optionally present substituents are provided below.

The substituents may be one or more of a variety of groups selected from (but not limited to): -OR ', =o, =nr', =n-OR ', -NR' R "-SR ', -halogen, -SiR' R", -OC (O) R, -C (O) R, -CO ₂ R-C(O)NR'R”、-OC(O)NR'R”、-NR”C(O)R、-NR'-C(O)NR”R”'、-NR”C(O)OR'、-NR-C(NR'R”)＝NR”'、-S(O)R、-S(O) ₂ R'、-S(O) ₂ NR'R”、-NRSO ₂ R'、-CN、CF ₃ Fluorinated C _1-4 Alkyl and-NO ₂ The number is in the range of zero to (2 m '+1), where m' is the total number of carbon atoms in such groups. R ', R ", R'" and R "" each independently can refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. Other non-limiting examples of substituents include (C ₁ -C ₆ ) Alkyl, (C) ₂ -C ₈ ) Alkenyl group (C) ₃ -C ₈ ) Alkynyl, halogen, halo (C) ₁ -C ₆ ) Alkyl, hydroxy, -O (C) ₁ -C ₆ ) Alkyl, halo (C) ₁ -C ₆ ) Alkoxy, (C) ₃ -C ₈ ) Cycloalkyl, (C) ₆ -C ₁₀ ) Aryl, heterocyclyl, heteroarylAmino, cyano, nitro, (C) ₁ -C ₆ ) alkyl-OH, (C) ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) Alkyl, (C) ₁ -C ₆ ) Alkyl (C) ₆ -C ₁₀ ) Aryl, -C (O) (C ₁ -C ₆ ) Alkyl, -C (O) NR 'R', -S (O) (C) ₁ -C ₆ ) Alkyl, -S (O) NR 'R', -S (O) ₂ (C ₁ -C ₆ ) Alkyl, -S (O) ₂ NR'R”、-O(C ₁ -C ₆ ) alkyl-S (O) (C ₁ -C ₆ ) Alkyl, -O (C) ₁ -C ₆ ) alkyl-S (O) NR 'R', -O (C) ₁ -C ₆ ) alkyl-S (O) ₂ (C ₁ -C ₆ ) Alkyl and-O (C) ₁ -C ₆ ) alkyl-S (O) ₂ NR 'R'. As used herein, an "alkoxy" group is an alkyl group attached to the rest of the molecule through divalent oxygen.

For example, when a compound of the present disclosure includes more than one R group, each of the R groups is independently selected, and when more than one of these groups is present, each of the R ', R ", R'" and R "" groups is also independently selected. When R 'and R' are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR' R "is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. With respect to the above discussion of substituents, those of ordinary skill in the art will understand that the term "alkyl" is intended to include a group that includes a carbon atom bonded to a group other than hydrogen, such as haloalkyl (e.g., -CF ₃ and-CH ₂ CF ₃ ) And acyl (e.g., -C (O) CH) ₃ 、-C(O)CF ₃ 、-C(O)CH ₂ OCH ₃ Etc.).

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula-T-C (O) - (CRR') _q -a ring of U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted by formula-A- (CH) ₂ ) _r -substitution of substituents of B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S (O)) ₂ -、-S(O) ₂ NR' -or a single bond, and r is an integer of 1 to 4.

One of the single bonds of the novel ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the formula- (CRR ') S-X ' - (C "R '") d-, wherein S and d are independently integers from 0 to 3, and X ' is-O-, -NR ' -, -S-, S (O) -, -S (O) ₂ -or-S (O) ₂ NR' -. Substituents R, R', R "and R" may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

As used herein, the term "acyl" refers to an organic acid group wherein the-OH of the carboxyl group has been replaced with another substituent and has the general formula RC (=o) -wherein R is alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic group, as defined herein. Thus, the term "acyl" specifically includes aryl acyl groups such as 2- (furan-2-yl) acetyl) -and 2-phenylacetyl. Specific examples of acyl groups include acetyl and benzoyl. Acyl is also intended to include amide, -RC (=o) NR, ester, -RC (=o) OR ', ketone, -RC (=o) R', aldehyde and-RC (=o) H.

The terms "alkoxy" or "alkoxy" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O-and alkynyl-O-) group attached to a parent molecular moiety through an oxygen atom, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as previously described and may include C _1-20 (inclusive), straight, branched or cyclic, saturated or unsaturated oxo-hydrocarbon chains including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and n-pentoxy, neopentoxy, n-hexoxy and the like.

The term "alkoxyalkyl" as used herein refers to an alkyl-O-alkyl ether, such as methoxyethyl or ethoxymethyl.

"aryloxy" refers to an aryl-O-group, wherein aryl is as previously described, including substituted aryl. The term "aryloxy" as used herein may refer to a phenyloxy or hexyloxy group, and a phenyloxy or hexyloxy group substituted with an alkyl, substituted alkyl, halo, or alkoxy group.

"aralkyl" refers to an aryl-alkyl-group in which the aryl and alkyl groups are as previously described and include substituted aryl and substituted alkyl groups. Exemplary aralkyl groups include benzyl, phenethyl, and naphthylmethyl.

"aralkoxy" refers to an aralkyl-O-group, wherein aralkyl is as previously described. Exemplary aralkoxy groups are benzyloxy, i.e. C ₆ H ₅ CH ₂ -O-. Aralkoxy groups may be optionally substituted.

"alkoxycarbonyl" refers to an alkyl-O-C (=o) -group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and t-butoxycarbonyl.

"aryloxycarbonyl" refers to an aryl-O-C (=o) -group. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

"aralkoxycarbonyl" refers to an aralkyl-O-C (=o) -group. An exemplary aralkoxycarbonyl group is a benzyloxycarbonyl group.

"carbamoyl" means-C (=O) NH ₂ Is a compound having an amide group.

"alkylcarbamoyl" refers to an R ' RN-C (=o) group wherein one of R and R ' is hydrogen and the other of R and R ' is alkyl and/or substituted alkyl as previously described. "dialkylcarbamoyl" refers to an R 'RN-C (=o) -group, wherein each of R and R' is independently alkyl and/or substituted alkyl as previously described.

As used herein, the term "carbonyldioxy" refers to a carbonate group of the formula-OC (=o) -OR.

"acyloxy" refers to an acyl-O-group wherein the acyl group is as previously described.

The term "amino" refers to-NH ₂ A group and also refers to a nitrogen-containing group, as known in the art, that is derived from ammonia by replacement of one or more hydrogen groups with an organic group. Examples of the examplesIn terms of this, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic groups having acyl and alkyl substituents, respectively.

"aminoalkyl" as used herein refers to an amino group covalently bound to an alkylene linker. More specifically, the terms alkylamino, dialkylamino and trialkylamino as used herein refer to one, two or three alkyl groups, respectively, as defined previously, attached to a parent molecular moiety through a nitrogen atom. The term "alkylamino" refers to a group having the structure-NHR ', wherein R' is alkyl as previously defined; and the term dialkylamino refers to a group having the structure-NR 'R ", wherein R' and R" are each independently selected from the group consisting of alkyl. The term trialkylamino refers to a group having the structure-NR 'R "R'" wherein R ', R "and R'" are each independently selected from the group consisting of alkyl. In addition, R 'and/or R' "together may optionally be- (CH) ₂ ) _k Wherein k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidinyl, trimethylamino, and propylamine.

Amino is-NR 'R ", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The terms alkyl sulfide and thioalkoxy refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S-and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

"amide" refers to an acyl-NH-group, wherein the acyl group is as previously described. "aralkenyl" refers to an aroyl-NH-group, wherein aroyl is as previously described.

The term "carbonyl" refers to a-C (=o) -group and may include an aldehyde group represented by the general formula R-C (=o) H.

The term "carboxyl" refers to a COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

The term "cyano" refers to a-CN group.

The terms "halo", "halide" and "halogen" refer to fluoro, chloro, bromo and iodo.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Furthermore, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl. For example, the term "halo (C _1-4 ) Alkyl "includes, but is not limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The terms "haloalkyl" and "cyclic haloalkyl" refer to a cycloalkyl group having one or more halogens.

The term "hydroxy" refers to an-OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with an-OH group.

The term "thio" refers to a-SH group.

The term "oxo" refers to an oxygen atom that is doubly bonded to a carbon atom or doubly bonded to another element.

The term "nitro" refers to-NO ₂ A group.

The term "thio" refers to a compound as described hereinabove wherein a carbon or oxygen atom is replaced by a sulfur atom.

The term "sulfate" refers to-SO ₄ A group.

As used herein, the term thiol or thiol refers to a group of formula-SH.

More specifically, the term "sulfide" refers to a compound having a group of the formula-SR.

The term "sulfone" refers to a sulfone having sulfonyl groups-S (O ₂ ) A compound of R'.

The term "sulfoxide" refers to a compound having a sulfinyl-S (O) R.

The term ureido refers to the formula-NH-CO-NH ₂ Urea groups of (a).

Further, a structure generally represented by the following formula:

as used herein refers to a cyclic structure, such as, but not limited to, aliphatic and/or aromatic cyclic compounds of 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, and the like, including saturated cyclic structures, partially saturated cyclic structures, and unsaturated cyclic structures, comprising one substituent R group, wherein R groups may be present or absent, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the cyclic structure. The presence or absence of R groups and the number of R groups are determined by the value of the variable "n", which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group is substituted if more than one is on an available carbon of the ring structure but not on another R group. For example, the above structure (where n is 0-2) will comprise a compound group including (but not limited to):

etc.

The dashed line representing a bond in a cyclic ring structure indicates that the bond may or may not be present in the ring. That is, the dotted line representing a bond in the cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

(symbol)Representing the point of attachment of the moiety to the remainder of the molecule.

When a given atom of an aromatic or heterocyclic aromatic ring is defined as "absent," the named atom is replaced by a direct bond.

Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl" and "heterocycloalkyl", "aryl", "heteroaryl", "phosphonate", "sulfonate", and their optionally present divalent derivatives) is intended to include both substituted and unsubstituted forms of the specified groups. The optional substituents for each type of group are provided below.

The substituents of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl mono-and divalent derivative groups (including groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR ', =o, =nr', =n-OR ', -NR' R ', -SR', -halogen, -SiR 'R', -OC (O) R ', -C (O) R', -CO ₂ R'、-C(O)NR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)OR'、-NR-C(NR'R”)＝NR”'、-S(O)R'、-S(O) ₂ R'、-S(O) ₂ NR'R”、-NRSO ₂ R'、-CN、CF ₃ Fluorinated C _1-4 Alkyl and-NO ₂ The number is in the range of zero to (2 m '+1), where m' is the total number of carbon atoms in such groups. R ', R ", R'" and R "" each independently can refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. As used herein, an "alkoxy" group is an alkyl group attached to the rest of the molecule through divalent oxygen. For example, when a compound of the present disclosure includes more than one R group, each of the R groups is independently selected, and when more than one of these groups is present, each of the R ', R ", R'" and R "" groups is also independently selected. When R 'and R' are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR' R "is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. With respect to substituents In the discussion above, those of ordinary skill in the art will understand that the term "alkyl" is intended to include a group that includes a carbon atom bonded to a group other than hydrogen, such as a haloalkyl (e.g., -CF ₃ and-CH ₂ CF ₃ ) And acyl (e.g., -C (O) CH) ₃ 、-C(O)CF ₃ 、-C(O)CH ₂ OCH ₃ Etc.).

Exemplary substituents for aryl and heteroaryl groups (and divalent derivatives thereof) similar to those described above for alkyl groups vary and are selected from, for example: halogen, -OR ', -NR' R ', -SR', -SiR 'R', -OC (O) R ', -C (O) R', -CO ₂ R'、-C(O)NR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)OR'、-NR-C(NR'R”R”')＝NR””、-NR-C(NR'R”)＝NR”'、-S(O)R'、-S(O) ₂ R'、-S(O) ₂ NR'R”、-NRSO ₂ R', -CN and-NO ₂ 、-R'、-N ₃ 、-CH(Ph) ₂ Fluoro (C) _1-4 ) Alkoxy and fluoro (C) _1-4 ) Alkyl, number ranging from zero to the total number of open valencies on the aromatic ring system; and wherein R', R "," and R "may be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. For example, when a compound of the present disclosure includes more than one R group, each of the R groups is independently selected, and when more than one of these groups is present, each of the R ', R ", R'" and R "" groups is also independently selected.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula-T-C (O) - (CRR') _q -a ring of U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted by formula-A- (CH) ₂ ) _r -substitution of the substituents of the-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S (O) ₂ -、-S(O) ₂ NR' -or a single bond, and r is 1 toAn integer of 4.

One of the single bonds of the novel ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted by formula- (CRR') _s -X'-(C”R”') _d -substituent substitution, wherein S and d are independently integers from 0 to 3, and X 'is-O-, -NR', -S-, -S (O) ₂ -or-S (O) ₂ NR' -. Substituents R, R ', R "and R'" may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

As used herein, the term "acyl" refers to an organic acid group wherein the-OH of the carboxyl group has been replaced with another substituent and has the general formula RC (=o) -wherein R is alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or aromatic heterocyclyl as defined herein. Thus, the term "acyl" specifically includes aryl acyl groups such as 2- (furan-2-yl) acetyl) -and 2-phenylacetyl. Specific examples of acyl groups include acetyl and benzoyl. Acyl is also intended to include amide, -RC (=o) NR ', ester, -RC (=o) OR ', ketone, -RC (=o) R ', aldehyde and-RC (=o) H.

"aralkyl" refers to an aryl-alkyl group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenethyl, and naphthylmethyl.

"aralkoxy" refers to an aralkyl-O-group, wherein aralkyl is as previously described. Exemplary aralkoxy groups are benzyloxy, i.e. C ₆ H ₅ -CH ₂ -O-. Aralkoxy groups may be optionally substituted.

"carbamoyl" means-C (=O) NH ₂ Is a compound having an amide group. "alkylcarbamoyl" refers to an R ' RN-C (=o) -group wherein one of R and R ' is hydrogen and the other of R and R ' is alkyl and/or substituted alkyl as previously described. "dialkylcarbamoyl" refers to an R 'RN-C (=o) -group, wherein each of R and R' is independently alkyl and/or substituted alkyl as previously described.

As used herein, the term carbonyldioxy refers to a carbonate group of the formula-O-C (=o) -OR.

The term "amino" refers to-NH ₂ A group and also refers to a nitrogen-containing group, as known in the art, that is derived from ammonia by replacement of one or more hydrogen groups with an organic group. For example, the terms "acylamino" and "alkylamino" refer to having an acyl group, respectivelySpecific N-substituted organic groups of groups and alkyl substituents.

"aminoalkyl" as used herein refers to an amino group covalently bound to an alkylene linker. More specifically, the terms alkylamino, dialkylamino and trialkylamino as used herein refer to one, two or three alkyl groups, respectively, as defined previously, attached to a parent molecular moiety through a nitrogen atom. The term "alkylamino" refers to a group having the structure-NHR ', wherein R' is alkyl as previously defined; and the term dialkylamino refers to a group having the structure-NR 'R ", wherein R' and R" are each independently selected from the group consisting of alkyl. The term trialkylamino refers to a group having the structure-NR 'R "R'" wherein R ', R "and R'" are each independently selected from the group consisting of alkyl. In addition, R 'and/or R' "together may optionally be- (CH) ₂ ) _k -wherein k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidinyl, trimethylamino, and propylamino.

The term "carboxyl" -COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

The term "cyano" refers to a-C.ident.N group.

The term "halo", "halide" or "halogen" refers to fluoro, chloro, bromo and iodo. Furthermore, terms such as "haloalkyl" are intended to include monohaloalkyl as well as polyhaloalkyl. For example, the term "halo (C _1-4 ) Alkyl "is intended to include, but is not limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "hydroxy" refers to an-OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with an-OH group.

The term "thio" refers to a-SH group.

The term "oxo" refers to an oxygen atom doubly bonded to a carbon atom or doubly bonded to another element, including nitrogen doubly bonded to a pyridine ring to produce a pyridine N-oxide.

The term "nitro" refers to-NO ₂ A group, which may also be represented by-N ⁺ (＝O)-O ^- 。

The term "sulfate" refers to-SO ₄ A group.

As used herein, the term thiol or thiol refers to a group of formula-SH.

The term "sulfone" refers to a sulfone having sulfonyl groups-S (O ₂ ) A compound of R.

The term "sulfoxide" refers to a compound having a sulfinyl-S (O) R.

The term ureido refers to the formula-NH-CO-NH ₂ Urea groups of (a).

Throughout the specification and claims, a given formula or name shall encompass all tautomers, congeners and optical and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, which may be defined in absolute stereochemistry as (R) -or (S) -or D-or L-for amino acids, and individual isomers are contemplated within the scope of the present disclosure. The compounds of the present disclosure are not inclusive of those compounds known in the art to be too unstable to be synthesized and/or isolated. The present disclosure is intended to include compounds in racemic, non-racemic and optically pure forms. Optically active (R) -and (S) -or D-and L-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Where the compounds described herein contain an olefinic bond or other geometric asymmetric center, and unless specified otherwise, it is desirable that the compounds include the E geometric isomer and the Z geometric isomer.

Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of the structures; i.e. the R-configuration and S-configuration with respect to each asymmetric center. Thus, individual stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the disclosure.

It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, all of which are within the scope of the present disclosure. The term "tautomer" as used herein is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

Unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen is formed from deuterium orTritium substitution or carbon substitution ¹³ C or ¹⁴ C-enriched carbon-substituted compounds having the structures of the present invention are within the scope of the present disclosure.

The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound may use deuterium, for example ² H) The tritium is ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) Is radiolabeled with a radioisotope of the formula (I). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

The compounds of the present disclosure may exist in salt form, and particularly in pharmaceutically acceptable salt form. The present disclosure includes such salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulfate, mesylate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+) -tartrate, (-) -tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate and salts of amino acids such as glutamate. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like. When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in the absence of a solvent or in a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphoric acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted to base addition salts or acid addition salts.

The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.

The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equally applicable for the uses contemplated by the present invention and are intended to fall within the scope of the present disclosure.

In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the disclosed compounds in an ex vivo environment by chemical or biochemical means. For example, prodrugs can be slowly converted to the disclosed compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent.

The term "protecting group" refers to a chemical moiety that blocks some or all of the reactive moieties of a compound and prevents such moieties from participating in a chemical reaction until the protecting group is removed, such as those listed and described in John Wiley & Sons (1999), for example T.W.Greene, P.G.M.Wuts, protective Groups in Organic Synthesis, 3 rd edition. It may be advantageous (in case different protecting groups are employed), each (different) protecting group being removable in a different way. Protecting groups that cleave under disparate reaction conditions allow for differential removal of such protecting groups.

For example, the protecting groups can be removed by acid, base and hydrogenolysis. The groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of an amino group protected by a Cbz group (which can be removed by hydrogenolysis) and an Fmoc group (which is base labile). In the presence of amines blocked by acid labile groups (e.g., t-butyl carbamate) or by acid and base stable but hydrolytically removable carbamates, the carboxylic acid and hydroxyl reactive moieties can be blocked by base labile groups such as, but not limited to, methyl, ethyl, and acetyl.

The carboxylic acid and hydroxyl reactive moiety may also be blocked with a hydrolytically removable protecting group (e.g., benzyl), while the amine group capable of hydrogen bonding with the acid may be blocked with a base labile group such as Fmoc. The carboxylic acid reactive moiety may be blocked with an oxidatively removable protecting group, such as 2, 4-dimethoxybenzyl, while the co-existing amino group may be blocked with a fluoro-labile silane carbamate.

The allyl blocking group is suitable for use in the presence of an acid protecting group and a base protecting group, since the former is stable and can then be removed by a metal or pi-acid (pi-acid) catalyst. For example, the allyl-blocked carboxylic acid may be deprotected using a palladium (O) -catalyzed reaction in the presence of an acid-labile tert-butyl carbamate or a base-labile acetate amine protecting group. Yet another form of protecting group is a resin to which the compound or intermediate may be attached. As long as the residue is attached to the resin, the functional group is blocked and unreactive. Once released from the resin, the functional groups are available for reaction.

Typical blocking/protecting groups include, but are not limited to, the following moieties:

the terms "a" and "an" as used in the present application (including the claims) and "the" mean "one or more" following the convention of patent laws of long term. Thus, for example, reference to "a subject" includes a plurality of subjects unless the context clearly indicates otherwise (e.g., a plurality of subjects), and so forth.

Throughout the specification and claims, the term "comprise/include" is used in a non-exclusive sense, unless the context requires otherwise. Also, the term "include" and grammatical variants thereof are intended to be non-limiting such that recitation of items in a list is not to the exclusion of other like items that may be substituted or added to the listed items.

For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, amounts, characteristics, and other values used in the specification and claims are to be understood as being modified in all instances by the term "about", although the term "about" may not be expressly recited along with the value, quantity, or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not, and need not be, exact, but may be approximated and/or desirably greater or lesser depending upon the desired characteristics sought to be obtained by the presently disclosed subject matter, reflecting tolerances, conversion factors, rounding off, measurement error and the like and other factors known to those of ordinary skill in the art. For example, when referring to values, the term "about" may be meant to encompass variations of ±100% in some embodiments, ±50% in some embodiments, ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% from a specified amount, as such variations are suitable for performing the disclosed methods or employing the disclosed compositions.

Furthermore, when used in conjunction with one or more numbers or ranges of values, the term "about" is understood to mean all such numbers, including all numbers within a range, and the range is modified by extending boundaries above and below the stated values. The recitation of numerical ranges by endpoints includes all numbers subsumed within that range and any range within that range, e.g., all integers, including fractions thereof (e.g., recitation of 1 to 5 includes 1, 2, 3, 4, and 5, and fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, etc.).

Compounds of formula (I)

The invention provides for modulation, e.g. inhibition of voltage-gated Na _V 1.8 sodium channel active compound.

A. A first group of compounds

In certain embodiments, the compound has the structure of formula (I):

wherein:

R ₂ Is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ halogen, alkyl or alkoxy;

R ₄ halogen, alkyl or H;

x is CH or N; and is also provided with

Z is CH or N, and the Z is CH or N,

with the proviso that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound has the structure of formula (II):

wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₇ Is H, halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ A heterocyclic group in which each ring has 5 or 6 members, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclic group or moietyUnsaturated heterocyclyl, O-aryl in which each ring has 5 or 6 members, O-heteroaryl in which each ring has 5 or 6 members, O-cycloalkyl, O-cycloheteroalkyl, each of which is optionally substituted where the valences permit,

R ₈ h, C of a shape of H, C _1-3 Alkyl or C _3-5 A cycloalkyl group,

the limiting conditions are as follows:

x and Z may not both be CH; and is also provided with

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound has the structure of formula (III):

Wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

z is CH, N or N-O,

R ₇ Is-H. Halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ A carbocyclyl group in which each ring has 3 to 6 members, a heterocyclyl group in which each ring has 5 or 6 members, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group or a partially unsaturated heterocyclyl group in which each ring has 3 to 6 members, an O-aryl group in which each ring has 5 or 6 members, an O-heteroaryl group in which each ring has 5 or 6 members, an O-cycloalkyl group, an O-cycloheteroalkyl group, each of which is optionally substituted as the valence permits,

the limiting conditions are as follows:

W ₁ 、W ₂ 、W ₃ 、W ₄ and W is ₅ Not more than two of them are N;

X and Z may not both be CH,

or a pharmaceutically acceptable salt thereof.

The compounds of the invention may be enriched in isotopes at any position where the atomic mass is not otherwise specified. For example, the compound may have one or more hydrogen atoms replaced with deuterium or tritium atoms. Isotopic substitution or enrichmentMay be carried out at carbon, sulfur or phosphorus or other atoms. For example and without limitation, the fluorine atom may be ¹⁹ F enrichment, carbon atoms can be ¹⁴ C is enriched and the nitrogen atom may be ¹⁵ N enrichment. The compounds may isotopically substitute or enrich a given atom at one or more positions within the compound, or the compounds may isotopically substitute or enrich in all cases of a given atom within the compound.

In certain embodiments, the compound has the structure of formula (IV),

wherein:

y is N or CR ₁₃ ；

R ₁₂ 、R ₁₃ and R is ₁₄ Individually selected from: H. CF (compact flash) ₃ Halo, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkylOxy, haloalkoxy, nitro, cyano, -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH (CH) ₃ ) -cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH (-CH) ₃ ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH ₂ Hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR 'R' -NHSO ₂ R1, -NHC (=o) -alkyl-NH (c=o) NR' R ", spirocyclic-, morpholino-, pyrrolidinyl-, piperidinyl-, carbocyclyl-, heterocyclyl-, aryl-, or heteroaryl wherein the 5 or 6 ring member ring optionally comprises one or more N or S in the ring, wherein the substitution on the 5 or 6 ring member ring is selected from the group consisting of: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, -C (=o) -NH-alkyl, -C (=o) NH ₂ Cyano, CF ₃ 、CHF ₂ 、OCH ₃ 、OCF ₃ A fused heterocyclyl group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group, or a partially unsaturated heterocyclyl group, each of which is optionally substituted as the valence permits;

In selected embodiments, A is CH ₂ CF ₃ Or (b)

In another aspect, the present invention provides a compound of formula (V),

A and B are as described for formula (IV)

R ₂ As forDescribed by the formula (II)

R ₁₃ And R is ₁₄ As described for formula (IV)

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O.

B. A second group of compounds

The compounds have the structure of formula (I):

wherein:

R ₁ is-CN or-CF ₃ ；

R ₃ Is halogen, alkyl, alkoxy or-CD ₃ ；

e is CH or CF;

x is CH or N;

z is CH or N; and is also provided with

-CD ₃ In order to have a completely deuterated methyl group,

with the proviso that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) contain deuterated methyl (-CD) groups on the sulfonimide moiety ₃ ). However, for the case ofThe other atoms of the compound have no defined atomic mass. Thus, the compounds of the invention may be enriched in isotopes at any position where the atomic mass is not otherwise specified. For example, the compound may have one or more hydrogen atoms replaced with deuterium or tritium. Isotopic substitution or enrichment may be performed at carbon, sulfur or phosphorus or other atoms. For example and without limitation, the fluorine atom may be ¹⁹ F enrichment, carbon atoms can be ¹⁴ C is enriched and the nitrogen atom may be ¹⁵ N enrichment. The compounds may isotopically substitute or enrich a given atom at one or more positions within the compound, or the compounds may isotopically substitute or enrich in all cases of a given atom within the compound.

C. A third group of compounds

The compounds have the structure of formula (I):

wherein:

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

e is CH, CF or N;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N, N ⁺ O ^- Or CH;

each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

R ₃ Can be monohalogenated or dihaloSubstituted or trihalogenated C ₁ -C ₄ An alkyl group. R is R ₃ Can be-CF ₃ 。

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N,

or a pharmaceutically acceptable salt thereof.

D. A fourth group of compounds

The compounds have the structure of formula (I):

wherein:

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

e is CH or CF;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N or N ⁺ O ^- ，

Each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N;

or a pharmaceutically acceptable salt thereof.

E. A fifth group of compounds

In some embodiments, the presently disclosed subject matter provides a compound of formula (I):

wherein:

R ₃ Selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkoxy, substituted or unsubstitutedSubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, -NO ₂ ；

and pharmaceutically acceptable salts thereof.

In some embodiments of the compounds of formula (I), R ₁ Is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with one or more groups selected from the group consisting of: substituted or unsubstituted C ₁ -C ₈ An alkyl group; halogen; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1,2,3, 4, 5, 6, 7 and 8; -S-CF ₃ ；

R ₂ Selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of: unsubstituted or substituted C ₁ -C ₈ An alkyl group; halogen; cyano group; an oxo group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ and-CHF ₂ A group of groups; - (CH) ₂ ) _q -OHWherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; -NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; morpholinyl; oxazolyl; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl and R ₁₁ Is C ₁ -C ₄ Alkyl, provided that when Y is nitrogen and R ₂ R in the case of phenyl or pyridyl ₈ Not being-NR ₆ R ₇ ；

In certain embodiments, the compound of formula (I) comprises a compound of formula (II):

Wherein:

n is an integer selected from 0, 1, 2, 3, 4 and 5;

In some embodiments of the compounds of formula (II), R ₂ Selected from the group consisting of:

wherein:

m is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

R ₂₆ Halogen or cyano;

each R ₂₇ Independently and separatelySelected from the group consisting of: H. halogen, C ₁ -C ₈ Alkoxy, cyano and-NR ₆ R ₇ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Each R ₂₈ Independently H or C ₁ -C ₄ An alkyl group.

In certain embodiments of the compounds of formula (II), the compounds are of formula (II-a):

wherein:

R ₂ selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted with a substituent selected from the group consisting of: unsubstituted or substituted C ₁ -C ₈ An alkyl group; halogen; cyano group; an oxo group; a heterocycloalkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CH ₂ F and-CHF ₂ A group of groups; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; morpholinyl; oxazolyl; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) _2- R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl and R ₁₁ Is C ₁ -C ₄ An alkyl group;

R ₁₂ selected from halogen, -OR ₂₃ A group of components, wherein R ₂₃ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CH ₂ F and-CHF ₂ A group of groups; and is also provided with

R _12' Selected from H, halogen, -OR ₁₃ A group of components, wherein R ₁₃ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CH ₂ F and-CHF ₂ A group of groups.

In certain embodiments of the compounds of formula (II-a), aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridinyl N-oxide, pyridazinyl and pyrimidinyl.

In certain embodiments of the compounds of formula (II-a), R ₂ Selected from the group consisting of: (trifluoromethanesulfonyl) phenyl, 1,2, 4-triazolyl, 1, 3-benzothiazol-2-yl, 1, 3-benzothiazol-6-yl, 2-fluoro-5-methylsulfonylphenyl, 2-methoxy-4-pyridinyl, 2-methyl-4-pyridinyl, 3- (dimethylsulfamoyl) phenyl, 3- (methylsulfinylphenyl), 3- (N, S-dimethylsulfamoyl) phenyl, 3-carbamoylphenyl, 3-cyanophenyl, 3-dimethylsulfamoylphenyl, 3-methylsulfinylphenyl, 3-morpholinophenyl, 3-oxazol-5-ylphenyl, 3-pyridinyl, 4-cyanophenyl, 4-pyridinyl, 6-cyano-3-pyridinyl, 6-methyl-3-pyridinyl, dimethyl (oxo) - λ6-sulfinyl ]Amino group]Phenyl, pyrazolyl, pyridazin-4-yl, pyridazinyl, pyridin-4-yl, pyridinyl, pyrimidin-4-yl, pyrimidinyl and thiadiazolyl.

In some embodiments, the compound of formula (I) comprises a compound of formula (III):

wherein:

R ₂ selected from the group consisting of:

and is also provided with

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-a):

wherein:

R ₁ selected from the group consisting of phenyl, pyridinyl, and 1, 3-benzothiazol-4-yl, wherein the phenyl and pyridinyl may be unsubstituted or substituted with one or more of: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; and is also provided with

R ₃ And R is ₄ Is H or-CF ₃ The limitation is thatIf R is ₃ Is H, then R ₄ is-CF ₃ And if R ₄ Is H, then R ₃ is-CF ₃ 。

In certain embodiments of compounds of formula (IIIa), R ₁ Selected from the group consisting of: 2, 4-dichlorophenyl group, 4-difluoromethoxyphenyl group and 2-chloro-4-methoxyphenyl group.

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-b):

wherein:

In certain embodiments of the compounds of formula (IIIc), the compound is a compound of formula (III-c):

Wherein:

R ₁ is halogen, C ₁ -C ₈ Alkyl, -O-R ₅ One of themOr a plurality of substituted phenyl groups, wherein R ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3,4, 5, 6, 7 and 8.

In certain embodiments of the compounds of formula (IIIc), R ₁ Selected from the group consisting of: 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2, 4-dimethoxyphenyl, 2, 4-difluorophenyl and 3, 4-difluorophenyl.

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-d):

wherein:

R ₁ selected from the group consisting of phenyl, pyridinyl, and 1, 3-benzothiazol-4-yl, wherein the phenyl and pyridinyl may be unsubstituted or substituted with one or more of: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3,4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; and is also provided with

In certain embodiments of the compounds of formula (III-d), the compounds are compounds of formula (III-d'):

wherein R is ₁ Selected from the group consisting of: 4-trifluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 2-chloro-4-trifluoromethoxyphenyl group, 2, 4-dimethoxyphenyl group and 2, 4-difluorophenyl group.

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-e):

wherein:

In certain embodiments of the compounds of formula (III-e), the compounds are of formula (III-e'):

wherein R is ₁ Selected from the group consisting of: 4-difluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 2-chloro-4-trifluoromethoxyphenyl group, 2, 4-dimethoxyphenyl group and 2, 4-difluorophenyl group.

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-f):

wherein:

In certain embodiments of the compounds of formula (III-f), the compounds are compounds of formula (III-f'):

wherein:

R ₁ selected from the group consisting of: 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2, 4-difluorophenyl, 4-difluoromethoxyphenyl, 2, 4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3, 4-difluorophenyl and 2-chloro-4-fluorophenyl.

In certain embodiments of the compounds of formula (III), the compounds are of formula (III-g):

wherein:

R ₁ is thatWherein R is _2c Selected from the group consisting of H, C ₁ -C ₄ Alkyl, halogen and C ₁ -C ₄ Alkoxy groups; and R is _4c Selected from the group consisting of-OCF ₃ 、C ₁ -C ₄ Alkoxy and halogen; and is also provided with

R ₂ Selected from the group consisting of:

in certain embodiments of the compounds of formula (III-g), R ₁ Selected from the group consisting of:

in certain embodiments, the compound of formula (III-g) is selected from the group consisting of:

3- (3- (4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridine 1-oxide;

3- (3- (2, 4-dimethoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridine 1-oxide;

3- (3- (2-chloro-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridine 1-oxide;

3- (2-chloro-4- (trifluoromethoxy) phenoxy) -N- (pyridazin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-fluoro-2-methoxyphenoxy) -N- (pyridazin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (pyridazin-4-yl) -3- (4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazin-4-carboxamide;

3- (2, 4-dimethoxyphenoxy) -N- (pyridazin-4-yl) -6- (trifluoromethyl) pyridazin-4-carboxamide;

5- (3- (2, 4-dimethoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridazine 1-oxide;

5- (3- (4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridazine 1-oxide;

5- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridazine 1-oxide; and

5- (3- (2-chloro-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridazine 1-oxide.

In some embodiments, the compound of formula (I) comprises a compound of formula (IV):

wherein R is ₂ Selected from the group consisting of:

(iii)wherein R is _5b' Selected from H, halogen and C ₁ -C ₄ Alkyl groups;

(iv)wherein R is _4b Is H or halogen;

(v)wherein R is ₉ Is H or C ₁ -C ₄ An alkyl group; and

(vi)

in certain embodiments of the compounds of formula (IV), the compound is a compound of formula (IV-a):

in certain embodiments of the compounds of formula (IV-a), R ₂ Selected from the group consisting of:

in certain embodiments of the compounds of formula (IV-a), the compounds are selected from the group consisting of:

3- (2-chloro-4-fluorophenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3-ethylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3-methylsulfonyl-6-methyl-phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3-methylsulfonyl-6-fluoro-phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3-acetylphenyl) -3- (2-chloro-4-fluoro-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- [3- (hydroxymethyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- [ 3-cyanophenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (4-pyridyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (3-pyridyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (3-pyridinyl-N-oxide) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (4-pyridinyl-N-oxide) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (2-oxo-1H-pyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (2-fluoro-4-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (2-methyl-4-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (6-fluoro-3-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (6-chloro-3-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (1-methyl-2-oxo-4-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N-pyridazin-4-yl-6- (trifluoromethyl) pyridazin-4-carboxamide;

3- (2-chloro-4-fluoro-phenoxy) -N- (2-oxopyridazin-2-ium-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide; and

3- (2-chloro-4-fluoro-phenoxy) -N-pyrimidin-4-yl-6- (trifluoromethyl) pyridazine-4-carboxamide.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-b):

wherein:

R ₃ and R is ₄ Is H or-CF ₃ With the proviso that if R ₃ Is H, then R ₄ is-CF ₃ And if R ₄ Is H, then R ₃ is-CF ₃ ；

R _2b Selected from the group consisting of H, C ₁ -C ₄ Alkyl and halogen; and R is ₁₄ Is C ₁ -C ₄ An alkyl group;

R ₁₄ is C ₁ -C ₄ An alkyl group; and is also provided with

R ₁₅ Is O or NR ₁₀ Wherein R is ₁₀ Is H or C ₁ -C ₄ An alkyl group.

In certain embodiments of the compounds of formula (IV-b), R ₁ Selected from the group consisting of: phenyl, 4-fluorophenyl, 2, 4-dichlorophenyl, 2, 4-dimethylphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2, 5-difluorophenyl, 4-methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3, 4-difluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, 4- (2, 2-trifluoroethoxy) phenyl, 4- (trifluoromethylthio) phenyl, 2-dimethylAn alkylaminophenyl group, a 2-trifluoromethylphenyl group, a 2, 4-dimethoxyphenyl group, a 3,4, 5-trifluorophenyl group, a 3, 5-dichlorophenyl group, a 6-trifluoromethyl-3-pyridyl group, a 1, 3-benzothiazol-4-yl group, a 4-difluoromethoxyphenyl group, a 2-chloro-4-methoxyphenyl group and a 2-chlorophenyl group.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-c):

wherein:

R ₁ is thatWherein:

R _1a 、R _1b 、R _1c 、R _1d and R is _1e Each independently selected from the group consisting of: H. c (C) ₁ -C ₄ Alkyl, halogen, C ₁ -C ₄ Alkoxy, -OCF ₃ 、-OCHF ₂ 、-OCH ₂ F、-OCH ₂ CF ₃ and-NR ₅ R ₆ Wherein R is ₅ And R is ₆ Is C ₁ -C ₄ Alkyl, provided that R _1a 、R _1b 、R _1c 、R _1d And R is _1e At least one of which is not H; and

pharmaceutically acceptable salts thereof.

In certain embodiments of the compounds of formula (IV-c):

(i)R _4a is halogen; r is R _2a Selected from the group consisting of H, C ₁ -C ₄ Alkyl, halogen and C ₁ -C ₄ Alkoxy groups; r is R _3a Is H or halogen; r is R _5a Is H or halogen; and R is _6a Is H;

(ii)R _2a and R is _4a Each is C ₁ -C ₄ An alkoxy group;

(iii)R _4a is-OF ₃ ；R _2a Selected from H, halogen and C ₁ -C ₄ Alkyl group；R _3a And R is _6a Each is H; r is R _5a Is H or halogen;

(iv)R _4a is-OCHF ₂ ；R _2a Selected from H, halogen and C ₁ -C ₄ Alkyl groups; r is R _3a And R is _6a Each is H; r is R _5a Is H or halogen;

(v)R _4a is-OCH ₂ F；R _2a Selected from H, halogen and C ₁ -C ₄ Alkyl groups; r is R _3a And R is _6a Each is H; r is R _5a Is H or halogen;

(vi)R _4a is-OCH ₂ F ₃ ；R _2a Selected from H, halogen and C ₁ -C ₄ Alkyl groups; r is R _3a 、R _5a And R is _6a Each is H;

(vii)R _3a is halogen; r is R _2a Is H or halogen; r is R _4a And R is _5a Is H; and R is _6a Is H or halogen; and

(viii)R ₂ is-NR ₅ R ₆ The method comprises the steps of carrying out a first treatment on the surface of the And R is _3a 、R _4a 、R _5a And R is _6a Each is H.

In certain embodiments of the compounds of formula (IV-c), R ₁ Selected from the group consisting of:

in certain embodiments of the compounds of formula (IV-c), the compounds are selected from the group consisting of:

3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-difluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dichlorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dimethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-trifluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-difluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-fluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-difluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-trifluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (2, 2-trifluoroethoxy) phenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4- (2, 2-trifluoroethoxy) phenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4-trifluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4-difluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4-fluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4-trifluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4-difluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4-fluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4- (2, 2-trifluoroethoxy) phenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3, 4-difluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3, 4, 5-trifluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3, 6-difluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 3-difluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-3-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3-fluoro-4-trifluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3-fluoro-4-difluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3-fluoro-4-fluoromethoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-chloro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide; and

3- (2-dimethylaminophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-d):

wherein:

R ₁ is thatWherein:

pharmaceutically acceptable salts thereof.

In certain embodiments of the compounds of formula (IV-d):

(ii)R _2a and R is _4a Each is C ₁ -C ₄ An alkoxy group;

(iii)R _4a is-OF ₃ ；R _2a Selected from H, halogen and C ₁ -C ₄ Alkyl groups; r is R _3a And R is _6a Each is H; r is R _5a Is H or halogen;

In certain embodiments of the compounds of formula (IV-d), R ₁ Selected from the group consisting of:

in certain embodiments of the compounds of formula (IV-d), the compound is selected from the group consisting of:

3- (4-fluoro-2-methylphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-difluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dichlorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dimethoxyphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (difluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (fluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (fluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (methylsulfonyl) phenyl) -3- (4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (methylsulfonyl) phenyl) -3- (4- (2, 2-trifluoroethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4- (2, 2-trifluoroethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -2-fluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-fluoro-4- (fluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -2-methylphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (fluoromethoxy) -2-methylphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-methyl-4- (2, 2-trifluoroethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3, 4-difluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) -3- (3, 4, 5-trifluorophenoxy) pyridazine-4-carboxamide;

3- (2, 5-difluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 3-difluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-3-fluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3-fluoro-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -3-fluorophenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3-fluoro-4- (fluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-chloro-2-methoxyphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide; and

3- (2- (dimethylamino) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-e):

wherein:

R ₃ selected from the group consisting of: -CF ₂ H、-CH ₂ F. Halogen, -OCF ₃ 、-OCHF ₂ 、-OCFH ₂ Cyclopropyl, branched or straight-chain C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, cyano, nitro, -SCF ₃ And SF (sulfur hexafluoride) ₅ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ₄ Selected from H and branched or straight chain C ₁ -C ₄ Alkyl groups.

In certain embodiments of the compounds of formula (IV-e), the compounds are selected from the group consisting of:

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (difluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (fluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-chloro-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethoxy) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (difluoromethoxy) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (fluoromethoxy) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-bromo-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-cyclopropyl-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-tert-butyl-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-isopropyl-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-methyl-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -5, 6-dimethyl-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-methoxy-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -5-methyl-6-methoxy-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-cyano-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6-nitro-pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- ((trifluoromethyl) thio) pyridazine-4-carboxamide; and

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (pentafluoro-l 6-sulfanyl) pyridazine-4-carboxamide.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-f):

wherein:

R ₁ is thatWherein:

R _1a 、R _1b 、R _1c 、R _1d and R is _1e Each independently selected from the group consisting of: H. c (C) ₁ -C ₄ Alkyl, halogen, C ₁ -C ₄ Alkoxy, -OCF ₃ 、-OCHF ₂ 、-OCH ₂ F、-OCH ₂ CF ₃ and-NR ₅ R ₆ Wherein R is ₅ And R is ₆ Is C ₁ -C ₄ Alkyl, provided that R _1a 、R _1b 、R _1c 、R _1d And R is _1e At least one of which is not H.

In certain embodiments of the compounds of formula (IV-f):

(ii)R _2a is C ₁ -C ₄ Alkoxy and R _4a Selected from C ₁ -C ₄ Alkoxy and halogen;

In certain embodiments of the compounds of formula (IV-f), R ₁ Selected from the group consisting of:

in certain embodiments of the compounds of formula (IV), the compounds are selected from the group consisting of:

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-difluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4-fluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dichlorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 4-dimethoxyphenoxy) -N- (3- (N, S-dimethylsulfinyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (trifluoromethoxy) phenoxy) -N- (3- (N, S-dimethylsulfinyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (difluoromethoxy) phenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-4- (fluoromethoxy) phenoxy) -N- (3- (N, S-dimethylsulfinyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethylsulfinyl) phenyl) -3- (4- (fluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide hydrochloride;

3- (4- (difluoromethoxy) phenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethylsulfinyl) phenyl) -3- (4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethylsulfinyl) phenyl) -3- (4- (2, 2-trifluoroethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (2-fluoro-4- (2, 2-trifluoroethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (2-fluoro-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -2-fluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (2-fluoro-4- (fluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (2-methyl-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -2-methylphenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

N- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (4- (fluoromethoxy) -2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (2-methyl-4- (2, 2-trifluoroethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (3, 4-difluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -6- (trifluoromethyl) -3- (3, 4, 5-trifluorophenoxy) pyridazine-4-carboxamide;

3- (2, 5-difluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2, 3-difluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2-chloro-3-fluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (3-fluoro-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4- (difluoromethoxy) -3-fluorophenoxy) -N- (3- (N, S-dimesyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (3-fluoro-4- (fluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (4-chloro-2-methoxyphenoxy) -N- (3- (N, S-dimethylsulfoxide) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide;

3- (2- (dimethylamino) phenoxy) -N- (3- (N, S-dimethyl-sulfinyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide; and

n- (3- (N, S-dimethyl-sulfinyl) phenyl) -3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide.

In certain embodiments of the compounds of formula (IV), the compounds are of formula (IV-g):

wherein:

R ₁ selected from the group consisting of: 4-difluoromethoxyphenyl, 2, 4-dimethoxyphenyl and 2, 4-difluorophenyl;

R ₂₀ is C ₁ -C ₄ An alkyl group; and is also provided with

R ₂₁ Is H or C ₁ -C ₄ An alkyl group.

In other embodiments, the presently disclosed subject matter provides the use of a compound of formula (I-IV) for the manufacture of a medicament for treating Na in a subject suffering from such a disorder _v 1.8 an agent that increases activity or expression of a related condition, disease or disorder.

F. Composition and method for producing the same

The present invention provides pharmaceutical compositions, such as those described above, comprising a compound of the present invention. The pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melt, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the compound admixed with pharmaceutically acceptable non-toxic excipients which are suitable for use in the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricants, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be employed. It may also be found in U.S. Pat. nos. 4,256,108; the techniques described in nos. 4,166,452 and 4,265,874 are covered, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for controlled release. The preparation and administration of compounds is discussed in U.S. patent No. 6,214,841 and U.S. publication No. 2003/0232877, the contents of which are incorporated herein by reference.

Formulations for oral use may also be presented as hard gelatin capsules wherein the compound is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules wherein the compound is mixed with water or an oily medium, for example peanut oil, liquid paraffin, or olive oil.

In cases where control of gastrointestinal hydrolysis of the compounds is sought, alternative oral formulations may be achieved using controlled release formulations in which the compounds of the present invention are encapsulated in an enteric coating.

The aqueous suspension may contain the compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersants or wetting agents, for example naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecyl ethoxycetyl alcohol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example sucrose or saccharin.

Oily suspensions may be formulated by suspending the compound in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those described above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. For example, suitable dispersing or wetting agents and suspending agents, such as sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils, such as liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example, acacia or tragacanth; naturally occurring phospholipids, such as soybean, lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and agents for flavouring and/or colouring. The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Particularly acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

In certain embodiments, the formulation is a slow release formulation. In certain embodiments, the formulation is not a slow release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation is free of particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation is free of polymeric interfacial stabilizers. In certain embodiments, the formulation is not an aqueous suspension.

The compositions may be formulated for administration by a particular mechanism. The compositions may be formulated for oral, intravenous, enteral, parenteral, transdermal, buccal, topical, nasal or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug eluting stent or balloon equivalent).

The compositions may be formulated as a single daily dose. The composition may be formulated for multiple daily doses, for example, two, three, four, five, six or more daily doses.

In another aspect, the invention provides a pharmaceutical composition comprising one or more compounds of the invention alone or in combination with one or more additional therapeutic agents, in admixture with a pharmaceutically acceptable excipient. One of ordinary skill in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the above compounds. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of the active compounds prepared with relatively non-toxic acids or bases depending on the particular substituent moiety present on the compounds described herein. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either in the absence of a solvent or in a suitable inert solvent, or by ion exchange, whereby one basic counter ion (base) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like.

When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in the absence of a solvent or in a suitable inert solvent or by ion exchange whereby one acidic counter ion (acid) in the ion complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphoric acid, and salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and the like. Also included are salts of amino acids such as arginine and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., berge et al, pharmaceutical salts (Pharmaceutical Salts), journal of pharmaceutical science (Journal of Pharmaceutical Science), 1977,66,1-19). Certain specific compounds of the present disclosure contain basic and acidic functionalities that allow the conversion of these compounds to base addition salts or acid addition salts.

Thus, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, for example, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium ethylenediamine tetraacetate, camphorsulfonate (camsylate), carbonate, citrate, ethylenediamine tetraacetate, ethanedisulfonate, etoate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, hydantoin phenylarsonate, hexylresorcinol (hexylesporinate), hydramine (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, hydroxyethylsulfonate (isethionate), lactate, maleate, mandelate, methanesulfonate, mucinate (mue), naphthalenesulfonate, nitrate, pamoate (embolate)), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, basic acetate, tannate, succinate, or tartrate. Other pharmaceutically acceptable salts are found, for example, in Remington, medical science and practice (Remington: the Science and Practice of Pharmacy) (20 th edition) Lippincott, williams & Wilkins (2000).

Depending on the particular condition being treated, these agents may be formulated in liquid or solid dosage forms and administered systemically or locally. The agent may be delivered, for example, in a timed release or sustained slow release form as known to those skilled in the art. Techniques for formulation and administration can be found in Remington, medical science and practice (20 th edition) Lippincott, williams & Wilkins (2000). Suitable pathways may include: oral, buccal, spray by inhalation, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, intrathecal, direct intraventricular, intravenous, intra-articular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections, or other modes of delivery.

For injection, the agents of the present disclosure may be formulated and diluted in an aqueous solution, for example, in a physiologically compatible buffer such as Hank's solution, ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

It is within the scope of the present disclosure to formulate the compounds disclosed herein using pharmaceutically acceptable inert carriers in order to practice the invention in dosages suitable for systemic administration. By appropriate choice of carrier and appropriate manufacturing criteria, the compositions of the present disclosure, particularly those formulated in solution, may be administered parenterally, for example by intravenous injection. The compounds may be readily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers may enable the compounds of the present disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject (e.g., a patient) to be treated.

For nasal or inhalation delivery, the agents of the present disclosure may also be formulated by methods known to those of ordinary skill in the art, and may include, for example, but not limited to, examples of dissolved, diluted, or dispersed substances, such as saline, preservatives (e.g., benzyl alcohol), absorption promoters, and fluorocarbons.

Pharmaceutical compositions suitable for use in the present disclosure include compositions containing an effective amount of the active ingredient to achieve its intended use. Determination of effective amounts is well within the ability of those skilled in the art (particularly in light of the detailed disclosure provided herein). In general, compounds according to the present disclosure are effective over a wide dosage range. For example, in treating an adult human, dosages in the range of 0.01 to 1000mg, 0.5 to 100mg, 1 to 50mg, and 5 to 40mg per day are examples of dosages that may be used. Non-limiting doses are 10 to 30mg per day. The exact dosage will depend on the following: the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, the bioavailability of the compound, the absorption, distribution, metabolism and excretion (ADME) toxicity of the compound, and the preferences and experiences of the attending physician.

In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, including excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Formulations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions.

Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and, if necessary, processing the mixture of granules after adding suitable auxiliaries to obtain tablets or dragee cores. Suitable excipients are in particular fillers, for example sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC) and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents can be added, for example crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, for example sodium alginate.

Dragee cores have a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel (carbopol gel), polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identifying or characterizing different combinations of active compound doses.

Pharmaceutical formulations for oral use include co-insert capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). The co-formulated insert capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, for example fatty oils, liquid paraffin or liquid polyethylene glycols (PEG). In addition, stabilizers may be added.

G. Methods of treating conditions

The invention provides methods of treating a condition in a subject using a compound of the invention. These methods are applicable to treatment and voltage-gated Na _V 1.8 abnormal (e.g. increased) activity of sodium channels. With Na and Na _V 1.8 Activity-increasing associated conditions and use of Na _V 1.8 treatment of such conditions is known in the art and described, for example, in International patent publication Nos. WO 2020/014243, WO 2020/014246, WO 2020/092187, the contents of each of which are incorporated herein by reference.

The condition may be, for example and without limitation, abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itching, acute pain with severe trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, idiopathic reactions, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burns, oral glowing syndrome, calcium pyrophosphate deposition disease, cervicales headache, shaggy's neurogenic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic lower back pain, chronic pancreatitis, chronic post-traumatic headache, chronic extensive pain, cluster headache, complex regional pain syndrome, continuous unilateral facial pain with additional episodes contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic hyperosteogeny, intervertebral disc degenerative pain, distal Sensory Polyneuropathy (DSP) associated with high activity antiretroviral therapy (HAART), eulls-Louis syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, fabry disease, facet joint syndrome, lumbar surgery failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngalgia, glossopharyngeal neuropathy degenerative pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, limb bone striated hypertrophy, migraine, multiple sclerosis, musculoskeletal injury, myofascial orofacial pain, post-ischemic neurodegeneration, type II neurofibromatosis, neuropathic eye pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, overactive bladder, congenital thick nail disease, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful arthroplasty, pancreatitis, parkinson's disease, paroxysmal extreme pain, pemphigus, peri-operative pain, peripheral neuropathy, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, chronic pain rheumatalgia, postherpetic neuralgia, mastectomy pain syndrome, postoperative pain, post-stroke pain, postoperative pain, postthoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, peripheral neuropathy induced by radiotherapy, raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disease, tension headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and neck whiplash.

Methods of treating a condition in a subject may comprise providing a composition of the invention to a subject. The composition may be provided to the subject by any suitable route or mode of administration. For example, and without limitation, the composition may be provided buccally, transdermally, enterally, intraarterially, intramuscularly, ocularly, intravenously, nasally, orally, parenterally, pulmonary, rectally, subcutaneously, topically, transdermally, by injection, or by implantable medical device.

The compositions may be provided according to a dosing regimen. The dosing regimen may include one or more of dosing, dosing frequency, and duration.

The doses may be provided at any suitable time interval. For example, and without limitation, doses may be provided once daily, twice daily, three times daily, four times daily, five times daily, six times daily, eight times daily, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once weekly, twice weekly, three times weekly, four times weekly, or five times weekly.

The dosage may be provided in a single dose, i.e., the dosage may be provided in the form of a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in divided doses, i.e. the dose may be provided in the form of a plurality of tablets, capsules, pills, etc.

Administration may be for a defined period of time. For example, and without limitation, a dose may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, or longer.

In some embodiments, the presently disclosed subject matter provides a method for regulating Na _v 1.8 sodium ion channel, comprising administering to a subject in need thereof a modulating effective amount of a compound disclosed herein to the subject.

In other embodiments, the presently disclosed subject matter provides for inhibition of Na _v 1.8, comprising administering to a subject in need thereof an effective inhibiting amount of a compound disclosed herein.

As used herein, the terms "inhibit" and grammatical derivatisation refer to blocking, partially blocking, interfering, reducing or decreasing Na in a subject of a compound of the disclosure, e.g., a compound of formula (I-IV) of the disclosure _v 1.8 activity or expression ability. Thus, those of ordinary skill in the art will appreciate that the term "inhibit" encompasses a complete and/or partial reduction in channel function, e.g., by at least 10%, in some embodiments by at least 20%, 30%, 50%, 75%, 95%, 98% and up to and including 100%.

In certain embodiments, the presently disclosed subject matter provides a method for treating and inhibiting Na _v 1.8 methods of increasing activity or expression of a related condition, disease or disorder. In a more particular embodiment, with Na _v 1.8 an increased activity or expression associated condition, disease or disorder selected from the group consisting of: pain, especially inflammatory, visceral and neuropathic pain; neurological disorders, particularly multiple sclerosis; autism, especially peter hopkins syndrome; and mental disorders, and combinations thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In particular embodiments, the disease or condition is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, paroxysmal pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, or a combination thereof.

In other embodiments, the disease or condition is selected from the group consisting of: HIV-associated pain, HIV-treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, multiple Sclerosis (MS) -associated pain, amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, narcolepsy, myasthenia syndrome, myotonic, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-associated diseases, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, localized and systemic tonic seizures, restless leg syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, tachycardia and fibrillation.

In some embodiments, the disease or condition is pitchplains syndrome (PTHS).

The presently disclosed subject matter also includes the use of a compound disclosed herein for the manufacture of a medicament for treating Na in a subject afflicted with such a disorder _v 1.8 an agent that increases activity or expression of a related condition, disease or disorder.

The "subject" treated by the methods of the present disclosure in many embodiments thereof is desirably a human subject, but it is understood that the methods described herein are effective with respect to all vertebrate species intended to be included in the term "subject. Thus, a "subject" may include a human subject for medical purposes, e.g., for treatment of an existing condition or disease or prophylactic treatment to prevent onset of a condition or disease, or an animal subject for medical, veterinary or developmental purposes. Suitable animal subjects include mammals, including, but not limited to, primates, such as humans, monkeys, apes, etc.; bovine animals, such as cattle, bull, etc.; sheep, such as sheep; sheep subfamilies such as goats and the like; porcine animals such as pigs, porkers, and the like; equine animals, such as horses, donkeys, zebras, etc.; felines, including wild cats and domestic cats; canines, including dogs; a lagomorpha animal; including rabbits, hares, etc.; and rodents, including mice, rats, and the like. The animal may be a transgenic animal. In some embodiments, the subject is a human, including (but not limited to) fetal, neonatal, infant, pediatric, and adult subjects. Further, "subject" may include a patient suffering from or suspected of suffering from a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or collection of cells from a subject.

In general, an "effective amount" of an active agent or drug delivery device refers to the amount necessary to induce the desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of the agent or device may vary depending on factors such as: the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc.

The term "combination" is used in its broadest sense and means that at least two agents, more particularly, a compound disclosed herein and at least one analgesic agent, are administered to a subject; and optionally, one or more analgesic agents. More particularly, the term "combination" refers to the simultaneous administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, active agents may be combined and administered in a single dosage form, may be administered simultaneously in separate dosage forms, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., where it is desired to change one but not the other amount). A single dosage form may include additional active agents for treating a disease state.

Furthermore, the compounds described herein may be administered alone or in combination with adjuvants that enhance the stability of the compounds described herein; the administration of pharmaceutical compositions containing these compounds, alone or in combination with one or more analgesic agents, may be facilitated in certain embodiments, provided increased dissolution or dispersion, increased inhibitory activity, provided adjuvant therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower doses of conventional therapeutic agents, thus avoiding the potential toxicity and adverse side effects that would otherwise be incurred if those agents were used as monotherapy.

The timing of administration of the compounds disclosed herein and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved. Thus, the phrase "in combination with … …" refers to the administration of a compound disclosed herein and at least one additional therapeutic agent simultaneously, sequentially or a combination thereof. Thus, a subject administered a combination of a compound disclosed herein and at least one additional therapeutic agent may receive the compound from the compound disclosed herein and the at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially in either order on the same day or on different days), so long as the effect of the combination of the two agents is achieved in the subject.

When administered sequentially, the agents may be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or more of each other. In other embodiments, sequentially administered agents may be administered within 1, 5, 10, 15, 20 days or more of each other. When a compound selected from the compounds disclosed herein and at least one additional therapeutic agent is administered simultaneously, it may be administered to the subject in the form of a separate pharmaceutical composition each comprising a compound selected from the compounds disclosed herein or at least one additional therapeutic agent, or it may be administered to the subject in the form of a single pharmaceutical composition comprising both agents.

When administered in combination, the effective concentration of each of the agents that elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing the dose of one or more of the agents to be reduced relative to the dose that would be required when the agents were administered as a single agent. The effects of the multiple agents may be (but need not be) additive or synergistic. The agent may be administered multiple times.

In some embodiments, two or more agents may have a synergistic effect when administered in combination. As used herein, the terms "synergistic," "synergistically," and derivatives thereof (e.g., in "synergistic effect" or "synergistic combination" or "synergistic composition") refer to the case where the biological activity of a combination of compounds selected from the group consisting of compounds disclosed herein and at least one additional therapeutic agent is greater than the sum of the biological activities of the individual agents when administered individually.

The synergy can be expressed in terms of "Synergy Index (SI)", which can be generally determined by the method described in f.c. kull et al, applied microbiology (Applied Microbiology) 9,538 (1961), from the ratios determined as follows:

Q _a /Q _A +Q _b /Q _B =synergy index (SI)

Wherein:

Q _A component a concentration, which is the sole effect, which gives rise to an endpoint for component a;

Q _a component a concentration that is the endpoint of production in the mixture;

Q _B for the concentration of component B acting alone, which yields an endpoint for component B; and

Q _b component B concentration, which is the endpoint of production in the mixture.

In general, when Q _a /Q _A And Q _b /Q _B More than one, indicating antagonism. When the sum equals one, additivity is indicated. When the sum is less than one, a synergistic effect is indicated. The lower the SI, the greater the synergy exhibited by their particular mixtures. Thus, a "synergistic combination" has a higher activity than is possibleThe expected activity based on the activity observed when the individual components are used alone. Furthermore, a "synergistically effective amount" of components refers to the amount of a component necessary to cause a synergistic effect in, for example, another therapeutic agent present in the composition.

More particularly, in some embodiments, the methods of the present disclosure comprise co-administering to a subject a compound selected from the group consisting of compounds disclosed herein and/or pharmaceutically acceptable salts thereof with one or more compounds selected from the group consisting of one or more of:

Non-steroidal anti-inflammatory drugs (NSAIDs) including, but not limited to, aspirin (aspirin), diclofenac (dichlofenac), difused sodium (bifusinal), etodolac (etodolac), fenbufen (fenbufen), fenoprofen (fenoprofen), flubenoxacin (flufenisal), flurbiprofen (flubiprofen), ibuprofen (ibuproxafen), indomethacin (indomethacin), ketoprofen (ketoprofen), ketotorola acid (ketorolac), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic), meloxicam (meloxicam), nabumetone (naproxen), naproxen (naproxen), nimesulide (nifedipine), niflumifene (niflumiprofen), oxaprozin (oxazine), oxaprozin (ibuproxazin), ketoprofen (ketoprofen), and fluvalproine (thiozamate); opioid analgesics including, but not limited to, morphine (morph), heroin (hermaphrodine), hydromorphone (hydromorphone), oxymorphone (oxymorphone), levorphanol (levorphanol), levaroprofen (levalrphan), methadone (methadone), maidine (meperidine), fentanyl (fentanyl), cocaine (cocaine), codeine (codeine), dihydrocodeine (dihydrocodeine), oxycodone (oxycodone), hydrocodone (hydrocodone), propoxyphene (lipoxyphenne), nalmefene (nalmefene), naloxone (naloxone), naltrexone (naltrexone), buprenorphine (buprenorphine), buprenorphine (buprofen), buprofen (naloxone), buphine (nalmefene) and pentazone (nalmefene); barbiturates, including but not limited to, amobarbital (amobarbital), aplobitual (acrobarbital), butabarbital (butabar) bital), butabarbital (butabial), tolbutal (mephobarbital), methobarbital (methorbial), methobarbital (methohexital), pentobarbital (pentobarbital), phenobarbital (phenobartital), secobarbital (secobarbial), tabupival (talbutal), plug Mi Le (thiamylal), and thiopental (thiopental); benzodiazepines (benzodiazepines) including, but not limited to, chlorodiazepine epoxide (chlorodiazepine), cloazepine (clomazone), diazepam (diazepam), fraazepam (fluazepam), lorazepam (lorazepam), oxazepam (oxazepam), hydroxy diazepam (temazepam), and triazolam (triazolam); histamine H ₁ Antagonists including, but not limited to, diphenhydramine (diphenhydramine), bimine (pyrilamine), promethazine (promethazine), chlorofenicoline (chloroheniramine), and chlorocyclizine (chloromycelizine);

sedatives, including, but not limited to, glutethimide (glutethimide), tranquiline (meprobamate), mequindox (methaqualone), and chloral-bixazone (dichloralphenozone); skeletal muscle relaxants including, but not limited to, baclofen, myotonin (carisoprodol), chlorzoxazone, cyclobenzaprine, methocarbamol, and diphenhydramine (orthophenanadine);

NMDA receptor antagonists, including but not limited to dextromethorphan (dextromethorphan) or its metabolite dextrorphan (dextrorophan), ketamine (ketamine), memantine, pyrroloquinoline quinine (pyrroloquinoline quinine), cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine (budipine), EN-3231 @, andcombination formulations of morphine base with dextromethorphan), topiramate (topiramate), neramexane (neramexane) or pezifotel (perzinfotel) comprising an NR2B antagonist, such as ifenprodil, qu Suoluo (traxopradil) or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3, 4-dihydro-2 (1H) -quinolinone; transient receptor potential ion channel antagonists; alpha-adrenal glandElements including, but not limited to, doxazosin, tamsulosin, clonidine, guanadine, dexmedetomidine, modafinil, and 4-amino-6, 7-dimethoxy-2- (5-methane-sulfonamido-1, 2,3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline; tricyclic antidepressants, including, but not limited to, desipramine, imipramine, amitriptyline and nortriptyline. Anticonvulsants, including, but not limited to carbamazepine (carbazepine,) and the like >) Lamotrigine (lamotrigine), topiramate, lacosamide (lacosamide,)>) And valproate; tachykinin antagonists, in particular NK-3, NK-2 or NK-1 antagonists, including but not limited to (. Alpha.R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl]-8,9,10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4]Diazacycloocta [2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ]]Ethoxy-3- (4-fluorophenyl) -4-morpholinyl]-methyl group]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant, lanpitant, dabite or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ]]-methylamino group]-2-phenylpiperidine (2 s,3 s); muscarinic antagonists including, but not limited to, oxybutynin (oxybutynin), tolterodine (tolterodine), propiverine (propiverine), trospium chloride (tropsium chloride), darifenacin (darifenacin), solifenacin (tebuxine), temivalin (temiverine), and ipratropium; cyclooxygenase-2 selective (COX-2) inhibitors, including, but not limited to, celecoxib (celecoxib), rofecoxib (rofecoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), deracoxib (deracoxib), etaxib (etoricoxib), and Lu Miluo cocoa (lumiracoxib); coal tar analgesics including, but not limited to, paracetamol (paracetamol);

Spirit safetyThe fixing agent is used for fixing the components of the medicine, including, but not limited to, droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, flufenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, and combinations thereof Suonepiprazole (SONEPIPRazole), blonanserin (blonanserin), iloperidone (iloperidone), piropiperidone (Perospirone), lanopride (raclopride), zotepine (zotepine), bifeprunox (bifeprunox), asenapine (asenapine), lurasidone (lurasidone), amisulpride (amisulpride), balapidone (balapidone), baladone (palindore), irinoteline (eplivanfluene), osanetant (osanetant), rimonabant (rimonabant), microphone Lin Tan (meclinert),Or Sha Lizuo tan (sarizotan); vanilloid receptor agonists, including but not limited to resina fluororelin (resina metaxin) or beadkacin (civamide);

vanilloid receptor antagonists, including but not limited to capsaicine (capsazepine) or GRC-15300);

Beta-epinephrine: including, but not limited to, propranolol (propranolol); local anesthetics, including, but not limited to, mexiletine (mexiletine); corticosteroids including, but not limited to, dexamethasone (dexamethasone) and prane Lai Song (prednisone); 5-HT receptor agonists or antagonists, in particular 5-HT _1B / _1D Agonists, including but not limited to eletriptan (eletriptan), sumatriptan (sumatriptan), naratriptan (naratriptan), zolmitriptan (zolmitriptan), or rizatriptan (rizatriptan);

5-HT ₂ a receptor antagonists, including but not limited to R (+) -alpha- (2, 3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), irinotecan (eplivanserin), ketanserin (ketanserin) and pimavanserin (pimavanserin); liner of containerBase (nicotine) analgesics including, but not limited to, eplerenone (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-butan-1-amine (RJR-2403), (R) -5- (2-azacyclylmethoxy) -2-chloropyridine (ABT-594) and nicotine; alpha ₂ Delta ligands including, but not limited to, gabapentin (gabapentin)Gabapentin GR->Gabapentin, ai Naka ratio (enacarabin)/(5)>Pregabalin (pregabalin)/(pregabalin)>3-methylgabapentin, (1 [ alpha ]) ],3[α],5[α]) (3-amino-methyl-bicyclo [ 3.2.0)]Hept-3-yl) -acetic acid, (3 s,5 r) -3-aminomethyl-5-methyl-heptanoic acid, (3 s,5 r) -3-amino-5-methyl-octanoic acid, (2 s,4 s) -4- (3-chlorophenoxy) proline, (2 s,4 s) -4- (3-fluorobenzyl) -proline, [ (1 r,5r,6 s) -6- (aminomethyl) bicyclo [3.2.0]Hept-6-yl]Acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4]Oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]-methylamine, (3 s,4 s) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (3 s,5 r) -3-aminomethyl-5-methyl-octanoic acid, (3 s,5 r) -3-amino-5-methyl-nonanoic acid, (3 s,5 r) -3-amino-5-methyl-octanoic acid, (3 r,4r,5 r) -3-amino-4, 5-dimethyl-heptanoic acid and (3 r,4r,5 r) -3-amino-4, 5-dimethyl-octanoic acid; cannabinoid receptor ligands including, but not limited to, cannabidiol (cannabidol), KHK-6188; metabotropic glutamate subtype 1 receptor antagonists;

a serotonin reuptake inhibitor comprising an active ingredient, including but not limited to sertraline (sertraline), sertraline metabolite norsertraline (demethylertraline), fluoxetine (fluoxetine), norfluoxetine (norfluoxetine) (fluoxetine demethylate metabolite), fluvoxamine (fluvoxamine), paroxetine (paroxetine), sitagliptin (citalopram), fluvoxamine (citalopram), The metabolites of sitagliptin norsitagliptin, escitalopram (escitalopram), d, l-fluoroamphetamine (d, l-fenfluramine), femoxetine (femoetine), ifexixetine (ifexetine), cyano doxepin (cyanodothiabin), rituxidine (litoetine), dapoxetine (dapoxetine), nefazodone (nefazodone), cericlamine (cericlamine) and trazodone (trazodone); norepinephrine (norepinephrine) reuptake inhibitors including, but not limited to, maprotiline (maprotiline), rofepramine (lofepramine), mirtazapine (mirtazepine), oxaprotiline (oxaprotiline), non-levolamine (fezolamine), tomoxetine (tomoxetine), mianserin (mianserin), bupropion (buproprion), bupropion metabolite hydroxy bupropion, nomifensine (nomifensine), and viloxazine (viloxazine)In particular selective norepinephrine reuptake inhibitors, such as reboxetine (reboxetine), in particular (S, S) -reboxetine; double serotonin-norepinephrine reuptake inhibitors, including but not limited to venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite norclomipramine, duloxetine >Milnacipran and imipramine; rho kinase inhibitors; inducible Nitric Oxide Synthase (iNOS) inhibitors, including but not limited to S- [2- [ (1-iminoethyl) amino ]]Ethyl group]-L-homocysteine, S- [2- [ (L-iminoethyl) -amino ]]Ethyl group]-4, 4-dioxo-L-cysteine, S- [2- [ (1-iminoethyl) amino ]]Ethyl group]-2-methyl-L-cysteine, (2 s,5 z) -2-amino-2-methyl-7- [ (L-iminoethyl) amino]-5-heptenoic acid, 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl]Thio group]-S-chloro-S-pyridinecarbonitrile; 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl]Thio group]-4-chlorobenzonitrile, (2S, 4R) -2-amino-4- [ [ 2-chloro-5- (trifluoromethyl) phenyl ]]Thio group]-5-thiazolbutanol, 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl]Thio group]-6- (trifluoromethyl) -3-pyridinecarbonitrile, 2- [ [ (1 r,3 s) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl]Thio group]-5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl ]]Phenyl group]Thiophene-2-carboxamidine, NXN-462 and guanidinoethyl disulfide; acetylcholinesterase inhibitors, including but not limited to donepezil (donepezil);

prostaglandin E ₂ Subtype 4 antagonists include, but are not limited to, N- [ ({ 2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c) ]Pyridin-1-yl) phenyl]Ethyl } amino) -carbonyl]-4-methylbenzenesulfonamide and 4- [ (15) -1- ({ [ 5-chloro-2- (3-fluorophenoxy) pyridin-3-yl)]Carbonyl } amino) ethyl]Benzoic acid; leukotriene B4 antagonists including, but not limited to, 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl]Oxyphenoxy group]Pentanoic acid (ONO-4057) and DPC-11870; 5-lipoxygenase inhibitors, including but not limited to zileuton, 6- [ (3-fluoro-5- [ 4-methoxy-3, 4,5, 6-tetrahydro-2H-pyran-4-yl)]) Phenoxy-methyl]-1-methyl-2-quinolinone (ZD-2138) and 2,3, 5-trimethyl-6- (3-pyridylmethyl) -1, 4-benzoquinone (CV-6504);

sodium channel blockers, including but not limited to lidocaine (lidocaine), lidocaine plus tetracaine cream (ZRS-201), and eslicarbazepine acetate (eslicarbazepine acetate); 5-HT ₃ Antagonists, including but not limited to ondansetron (ondansetron); N-methyl-D-aspartate receptor antagonists; voltage-gated calcium channel blockers (e.g., N-type and T-type) including, but not limited to, ziconotide (zicoid), Z-160, (R) -2- (4-cyclopropylphenyl) -N- (1- (5- (2, 2-trifluoroethoxy) pyridin-2-yl) ethyl) acetamide;

KCNQ openers (e.g. KCNQ2/3 (K) _v 7.2/3)); TPRV 1 receptor agonists, including but not limited to capsaicinAnd pharmaceutically acceptable salts and solvates thereof; nicotinic receptor antagonists including, but not limited to, varenicline (varenicline); nerve growth factor antagonists, including, but not limited to, tanizumab (tanizumab); inner partPeptidase stimulators, including but not limited to senrebamiphene (senrebase); angiotensin II antagonists including, but not limited to EMA-401; />Tramadol ER (Tramadol ER,) and method of making same>) Tapentadol ER (Tapentadol ER,)>) The method comprises the steps of carrying out a first treatment on the surface of the PDE5 inhibitors including, but not limited to, 5- [ 2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (sildenafil)), (6R, 12 aR) -2,3,6,7,12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2',1':6,1]Pyrido [3,4-b ]]Indole-1, 4-dione (IC-351 or tadalafil), 2- [ 2-ethoxy-5- (4-ethyl-piperazine-1-yl-1-sulfonyl) -phenyl]-5-methyl-7-propyl-3H-imidazo [5,1-f][1,2,4]Triazin-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ]Pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one, 5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- [ 2-methoxyethyl ]]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one, 4- [ (3-chloro-4-methoxybenzyl) amino group]-2- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl]-N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4, 3-d)]Pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl]-4-propoxybenzene sulfonamide;

Na _V 1.7 blocking agents including, but not limited to XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, and blocking agents such as those disclosed in the following documents: WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613, WO2012/116440,WO2011026240, U.S. patent No. 8,883,840 or No. 8,466,188 or PCT/US2013/21535, the entire contents of each application being incorporated herein by reference; and

Na _V 1.7 blocking agents including, but not limited to, (2-benzyl spiro [3, 4-dihydropyrrolo [1, 2-a)]Pyrazine-1, 4' -piperidines ]-1 '-yl) - (4-isopropoxy-3-methyl-phenyl) methanone, 2-trifluoro-1- [1' - [ 3-methoxy-4- [2- (trifluoromethoxy) ethoxy ]]Benzoyl group]-2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]-ethanone, [ 8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1-,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- (4-isobutoxy-3-methoxy-phenyl) methanone, 1- (4-benzhydryl piperazin-1-yl) -3- [2- (3, 4-dimethylphenoxy) ethoxy]Propan-2-ol, (4-butoxy-3-methoxy-phenyl) - [ 2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, [ 8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- (5-isopropoxy-6-methyl-2-pyridinyl) methanone, (4-isopropoxy-3-methyl-phenyl) - [ 2-methyl-6- (1, 2-pentafluoroethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 5- [ 2-methyl-4- [ 2-methyl-6- (2, 2-trifluoroacetyl) spiro [3, 4-dihydropyrrolo- [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -carbonyl group]Phenyl group]Pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl) - [6- (trifluoromethyl) spiro [3, 4-dihydro-2H-pyrrolo [1,2-a ] ]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 2-trifluoro-1- [1' - [ 3-methoxy-4- [2- (trifluoromethoxy) ethoxy ]]Benzoyl group]-2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 2-trifluoro-1- [1' - (5-isopropoxy-6-methyl-pyridine-2-carbonyl) -3, 3-dimethyl-spiro [2, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 2-trifluoro-1- [1' - (5-isopentyloxy pyridine-2-carbonyl) -2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, (4-isopropoxy-3-methoxy-phenyl) - [ 2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, 2-trifluoro-1- [1' - (5-isopentyloxy pyridine-2-carbonyl) -2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]Ethyl ketone,1- [ (3S) -2, 3-dimethyl-1' - [4- (3, 3-trifluoropropoxymethyl) benzoyl]Spiro [3, -4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]-2, 2-trifluoro-ethanone, [ 8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]- [ 3-methoxy-4- [ (1R) -1-methylpropyloxy ]]Phenyl group]Methanone, 2-trifluoro-1- [1' - (5-isopropoxy-6-methyl-pyridine-2-carbonyl) -2, 4-dimethyl-spiro [3, 4-dihydropyrrolo [1,2-a ] ]Pyrazine-1, 4' -piperidines]-6-yl]Ethanone, 1- [1' - [ 4-methoxy-3- (trifluoromethyl) benzoyl ]]-2-methyl-spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-6-yl]-2, 2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl) - [ 2-methyl-6- (trifluoromethyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]Methanone, [ 2-methyl-6- (1-methylcyclopropane carbonyl) spiro [3, 4-dihydropyrrolo [1,2-a ]]-pyrazine-1, 4' -piperidines]-1' -yl]- [4- (3, 3-trifluoropropoxymethyl) phenyl ]]Methanone, 4-bromo-N- (4-bromophenyl) -3- [ (1-methyl-2-oxo-4-piperidinyl) sulfamoyl]Benzamide or (3-chloro-4-isopropoxy-phenyl) - [ 2-methyl-6- (1, 2-pentafluoroethyl) spiro [ 34-dihydropyrrolo [1,2-a ]]Pyrazine-1, 4' -piperidines]-1' -yl]A ketone.

In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from the group consisting of acetaminophen, an NSAID, an opioid analgesic, and combinations thereof, in combination with or without a pharmaceutically acceptable carrier.

In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt, with or without a pharmaceutically acceptable carrier, and one or more additional therapeutic agents for treating pain. In one embodiment, the additional therapeutic agent is selected from the group consisting of acetaminophen, NSAIDs (e.g., aspirin, ibuprofen, and naproxen), and opioid analgesics. In another embodiment, the additional therapeutic agent is acetaminophen. In another embodiment, the additional therapeutic agent is an NSAID. In another embodiment, the additional therapeutic agent is an opioid analgesic.

V. examples

The following examples are included to provide guidance to those of ordinary skill in the art in practicing representative embodiments of the presently disclosed subject matter. In view of the present invention and the level of ordinary skill in the art, it will be appreciated by those of ordinary skill in the art that the following examples are intended to be illustrative only and that many variations, modifications, and changes may be employed without departing from the scope of the presently disclosed subject matter. The following synthetic descriptions and specific examples are intended for illustrative purposes only and should not be construed as limiting in any way to make the compounds of the present disclosure by other methods.

A. Examples of the first group of Compounds

Example 1

Methods for preparing the compounds of the present invention and intermediates used in the synthesis thereof are provided in the following general synthetic schemes and specific synthetic procedures. Unless otherwise indicated, chemicals were purchased from commercial suppliers and used as received. Otherwise, their preparation is convenient and known to those of ordinary skill in the art, or it is referred to or described herein. The abbreviations are consistent with those in ACS style guidelines. By "drying" is meant oven/dryer drying. Unless otherwise indicated, the solvents were ACS grade.

Unless indicated otherwise, all reactions were performed under dry nitrogen or dry argon positive pressure in flame-dried or oven-dried glassware and magnetically stirred. Unless otherwise indicated, chemicals were purchased from commercial suppliers and used as received. The yield is not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or ChemAxon.

A0.25 mm silica gel 60F254 plate (available from EMD MILLIPORE) was used ^TM ) The reaction was monitored by Thin Layer Chromatography (TLC). Purification was performed with CombiFlash NextGen 300 automated flash chromatography system or purified using one of the preparative HPLC methods mentioned below. Analytical data was collected using one of the analytical methods described below.

Example 2

Preparation method 1 (P1): early acid process

Purification (METRP 004) (P1) LC was performed using a Waters Sunfire C18 column (30 mm. Times.100 mm,5 μm; temperature: room temperature) with injection volume of 1500. Mu.L at a flow rate of 40mL/min for 0.55 min at 100% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile), followed by 13.89 min with a 10-95% B gradient and 2.11 min. A second gradient of 95-10% B was then applied for 0.2min. UV spectra were recorded at 215nm using Gilson detector.

Preparation method 2 (P2): acid standard method

Purification (METRP 001) (P2) LC was performed using a Waters Sunfire C18 column (30 mm. Times.100 mm,5 μm; temperature: room temperature) with an injection volume of 1500. Mu.L at a flow rate of 40mL/min for 0.55 min at 30% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile), followed by a gradient of 30-95% B for 10.45 min and for 2.10 min. A second gradient of 95-30% B was then applied for 0.21min. UV spectra were recorded at 215nm using Gilson detector.

Preparation method 3 (P3): alkaline early stage method

Purification (METRP/Prep 002) (P3) LC was performed using a Waters X-Bridge C18 column (30 mm. Times.100 mm,5 μm; temperature: room temperature) with an injection volume of 1500. Mu.L at a flow rate of 40mL/min for 0.55 min at 10% B (A=0.2% ammonium hydroxide/water; B=0.2% ammonium hydroxide/acetonitrile), followed by a gradient of 10-95% B for 13.89 min and for 2.11 min. A second gradient of 95-10% B was then applied for 0.2min. UV spectra were recorded at 215nm using Gilson detector.

Preparation method 4 (P4): alkaline standard method

Purification (METRP 003) (P4) LC was performed using a Waters X-Bridge C18 column (30 mm. Times.100 mm,5 μm; temperature: room temperature) with injection volume of 1500. Mu.L at a flow rate of 40mL/min for 0.55 min at 30% B (A=0.2% ammonium hydroxide/water; B=0.2% ammonium hydroxide/acetonitrile) followed by a gradient of 30-95% B for 10.45 min and for 2.10 min. A second gradient of 95-30% B was then applied for 0.21min. UV spectra were recorded at 215nm using Gilson detector.

LCMC was collected and analyzed using one of the following methods:

method 1 (M1): acidic IPC method (METRR 1410-MS17, MS18, MS 19)

Analytical (MET/CR/1410) (M1) HPLC-MS was performed using a Kinetex core-shell C18 column (2.1 mm. Times.50 mm,5 μm; temperature: 40 ℃) with 3. Mu.L injection volume at 1.2mL/min for 1.2 min at 5-100% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile) followed by 0.1 min at 100% B. A second gradient of 100-5% B was then applied for 0.01min and held for 0.39 min. UV spectra were recorded at 215nm using SPD-M20A PDA detector, spectral range: 210-400nm. Mass spectra were obtained using 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 3 (M3): alkaline IPC method (MET-uPLC-AB-2005-MS 16, MSQ 5)

Using WatersThe BEHTM C18 column (2.1 mM. Times.30 mM,1.7 μm; temperature: 40 ℃) was subjected to analytical (MET/uPLC/AB 2005) (M14) uHPLC-MS, wherein 1-100% B (A=2 mM ammonium bicarbonate/water, buffered to pH 10; B=acetonitrile) was injected at a flow rate of 1.0mL/min for 1.1 min at an injection volume of 1. Mu.L followed by 0.25 min at 100% B. A second gradient of 100-1% b was then applied for 0.05min and held for 0.4 min. UV spectra were recorded at 215nm using a Waters ACQUITY PDA detector, spectral range: 200-400nm. Mass spectra were obtained using a Waters Quattro Premier XE mass spectrum detector or Waters SQD 2. Data was integrated and reported using Waters MassLynx and OpenLynx software.

Method 4 (M4): acid final analysis method (METRR-uPLC-AB 101-MSQ1, MSQ2, MSQ 4)

Analytical (MET/uPLC/AB 101) (M4) uHPLC-MS was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm. Times.100 mm,1.7 μm; temperature: 40 ℃) with 5-100% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile) at a flow rate of 0.6mL/min for 5.3 minutes at an injection volume of 1. Mu.L followed by 100% B for 0.5 minutes. A second gradient of 100-5% b was then applied for 0.02min and held for 1.18 min. UV spectra were recorded at 215nm using a Waters ACQUITY PDA detector, spectral range: 200-400nm, ELS data was collected on a Waters ACQUITY ELS detector when reported. Mass spectra were obtained using Waters SQD or Waters ACQUITY QDA. Data was integrated and reported using Waters MassLynx and OpenLynx software.

Method 5 (M5): acid final analysis method (METRR 1416-MS18, MS 19)

Analytical (MET/CR/1416) (M5) HPLC-MS was performed using a Waters Atlantis dC column (2.1 mm. Times.100 mm,3 μm; temperature: 40 ℃) with 5-100% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile) at a flow rate of 0.6mL/min for 5 minutes at an injection volume of 3. Mu.L followed by 100% B for 0.4 minutes. A second gradient of 100-5% b was then applied for 0.02min and held for 1.58 min. UV spectra were recorded at 215nm using SPD-M20A PDA detector, spectral range: 210-400nm. Mass spectra were obtained using 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): alkaline final analysis method (MET-uPLC-AB 105-MS16, MSQ 5)

Using WatersThe BEHTM C18 column (2.1 mM. Times.100 mM,1.7 μm; temperature: 40 ℃) was subjected to analytical (MET/uPLC/AB 105) (M8) uHPLC-MS, wherein an injection volume of 1. Mu.L was maintained at a flow rate of 0.6mL/min for 5.3 min at 5-100% B (A=2 mM ammonium bicarbonate/water, buffered to pH 10; B=acetonitrile) followed by a duration of 0.5 min at 100% B. A second gradient of 100-5% b was then applied for 0.02min and held for 1.18 min. UV spectra were recorded at 215nm using a Waters ACQUITY PDA detector, spectral range: 200-400nm. Mass spectra were obtained using a Waters Quattro Premier XE mass spectrum detector or Waters SQD 2. Data was integrated and reported using Waters MassLynx and OpenLynx software.

Method 7

Mass spectral data was collected using a Waters Acquity H-class ultra-high pressure liquid chromatograph connected to a Waters Acquity TQD mass spectrometer. Samples were separated and resolved using a Acquity UPLC BEH C column (2.1X50 mm). Compounds were eluted from the column using a 10min linear solvent gradient: 0-0.5min,5% B;0.5-6.5min,100% B,6.5-7.5min;100% B,7.5-8.1min;5% B,8.1-10min;5% B. The solvent flow rate was 0.45mL/min. Solvent a is water and solvent B is acetonitrile. Mass spectra were collected in either positive or negative ion mode with the following parameters: 2.5kV capillary voltage; 25V sampling cone voltage; source temperature of 140 ℃; desolvation temperature of 400 ℃;800L/hr of nitrogen desolvation.

Unless otherwise indicated, in Bruker ^TM Recording on a 300MHz or 500MHz, 400MHz or 250MHz or on a Bruker Avance III HD 500MHz mass spectrometer, bruker Avance III HD 400MHz mass spectrometer ¹ H Nuclear Magnetic Resonance (NMR) spectroscopy. Chemical shift δ is recited in parts per million (ppm) relative to TMS and is calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to represent multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet), dt (doublet of triplet), dq (doublet of quartet), hep (heptadoublet), m (multiplet), pent (quintet), td (doublet of doublet), qd (quartet of doublet), app (obvious) and br. (broad). The coupling constant J is given closest to 0.1 Hz.

Example 3

The purification method is as follows:

preparation method 1 (P1): early acid process

Preparation method 2 (P2): acid standard method

Preparation method 3 (P3): alkaline early stage method

Preparation method 4 (P4): alkaline standard method

Example 4

Abbreviations and acronyms

When the following abbreviations are used herein, they have the following meanings:

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example 5

General synthetic scheme

The methods for preparing the compounds of the present invention are illustrated in the schemes and examples below. The present invention further provides a process for the preparation of compounds of structural formulae (I) and (II) as defined above. In some cases, the order in which the foregoing reaction schemes are carried out may be altered to facilitate the reaction or to avoid undesirable reaction products. The following exemplary compounds are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

Scheme 1

The compounds of formula (I) can be synthesized in a seven-step linear synthesis starting from heteroaromatic bischloroformates A-1 by using various substituted phenols in a base (e.g. K ₂ CO ₃ 、Cs ₂ CO ₃ Nucleophilic displacement of Cl adjacent to carboxylic acid in the presence of NaOH, KOH or other organic base) to give an intermediate of type a-2. The intermediate form A-2 may be further treated with nitromethane in DMSO using an organic base to produce A-3.A-3 can be converted to the corresponding iodo compound by treatment with HI (50%), HI (57%) or HI (40%) to give the form A-4 intermediate. R is differently substituted ₁ The groups can be introduced with the A-4 type intermediate by Pd-mediated or Cu-mediated coupling to produce the A-5 type intermediate. Formic acid of the A-6 intermediate can be prepared by hydrolyzing an ester of the A-5 intermediate using a base (e.g., aqueous NaOH, KOH or LiOH). Alternatively, the form A-6 intermediate may be prepared by treating the form A-5 intermediate with 1 to 6N aqueous HCl. The carboxylic acid (A-6) may be converted to the corresponding acid chloride and then reacted with 3- (substituted thio) aniline to give A-7. Alternatively, A-7 may use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) is prepared from carboxylic acid (a-6) and 3- (substituted thio) aniline in an organic solvent and a base (e.g. DIEA).The compounds of formula (I) may be prepared by reacting an intermediate of the type A-7 with ammonium carbonate and (diacetoxyiodo) benzene in an organic solvent, such as methanol.

Scheme 2

Form B-3 intermediates can be prepared in analogy to the procedure described for a-4 in scheme 1. The intermediate of form B-3 is further reacted with methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, TBAI, cuI using DMF or HMPA as solvent and heated at 25 ℃ to 120 ℃ for a period of 1 to 12 hours to give B-4. The acid intermediate (B-5) can be prepared from B-4 by a hydrolysis procedure similar to that described in scheme 1. Form B-6 intermediates can be prepared from the corresponding acids using standard coupling conditions described in scheme 1. The compounds of formula (II) can be prepared by treating B-6 with potassium hydrogen persulfate in an organic solvent or with mCPBA in DCM. Alternatively, the compound of formula (II) may be prepared from carboxylic acid (B-5) and an appropriately 3-substituted aniline using standard coupling conditions as described in scheme 1. The compounds of formula (II) may also be prepared by reacting an intermediate of type B-6 with ammonium carbonate and (diacetoxyiodo) benzene in an organic solvent, such as methanol.

Scheme 3

The compound of formula (III) can be prepared by using standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) is prepared from B-5 and a substituted aniline or heteroaryl aniline in an organic solvent and a base (e.g. DIEA).

Example 6

Specific synthesis:

Scheme 4, intermediates 1-5

3- (4-fluoro-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid

Reagents and conditions: a) 4-fluoro-2-methylphenol, K ₂ CO ₃ 、CH ₃ CN,80 ℃ for 3 hours; b) Nitromethane, et ₃ N, DMSO, room temperature, 48h; c) HI (57%), 55deg.C, 16h; d) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, TBAI, cuI, DMF,90 ℃ for 2h; e) LiOH, THF, H ₂ O (5:1), room temperature.

Intermediate 1

Step 1: 6-chloro-3- (4-fluoro-2-methylphenoxy) pyridazine-4-carboxylic acid methyl ester: 4-fluoro-2-methylphenol (3.01 g,23.8 mmol), 3, 6-dichloropyridazine-4-carboxylic acid methyl ester (4.70 g,22.7 mmol) and K ₂ CO ₃ (4.71 g,34.1 mmol) in CH ₃ The mixture in CN (47 mL) was stirred at 80℃for 3h. The reaction was cooled to room temperature, filtered, and taken up with CH ₃ CN (20 mL) was washed. The filtrate was concentrated in vacuo to give a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 15% etoac/heptane afforded the title compound methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (95.0%) as a pale yellow oil (4.10 g, 58%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.26(s,1H),7.29-7.20(m,2H),7.16-7.06(m,1H),3.94(s,3H),2.11(s,3H)。LC-MS：m/z：297/299[M+H] ⁺ (esi+), rt=4.26 LCMS method 5.

Intermediate 2

Step 2: 6-chloro-3- (4-fluoro-2-methylphenoxy) -5-methylpyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 6-chloro-3- (4-fluoro-2-methylphenoxy) pyridazine-4-carboxylate (1.20 g,4.04 mmol) in DMSO (3.6 mL) was added nitromethane (1.1 mL,20.2 mmol) and the mixture was stirred at room temperature for 30 min, triethylamine (0.85 mL,6.07 mmol) was added to the reaction and stirred at room temperature for 48 h. The reaction was diluted with water (100 mL) and brine (25 mL) and extracted with EtOAc (2X 50 mL). The organic layer was dried (MgSO ₄ ) Filtration and concentration under reduced pressure gave a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 100% etoac/heptane afforded the title compound (1.110 g, 85%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.26-7.19(m,2H),7.15-7.08(m,1H),3.99(s,3H),2.38(s,3H),2.08(s,3H)。LC-MS：m/z 310.95,312.9[M+H] ⁺ (esi+), rt=1.27 LCMS method 5.

Intermediate 3

Step 3:3- (4-fluoro-2-methylphenoxy) -6-iodo-5-methylpyridazine-4-carboxylic acid methyl ester:

a mixture of 6-chloro-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid methyl ester (1.10 g,3.54 mmol) in 55% aqueous hydrogen iodide (55%, 24mL,0.177 mol) was stirred at 40℃for 16h. The reaction was diluted with water (50 mL) and saturated sodium thiosulfate (100 mL) and extracted with EtOAc (2X 100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the title compound 3- (4-fluoro-2-methylphenoxy) -6-iodo-5-methylpyridazine-4-carboxylic acid methyl ester (42.0%) as a brown oil (1153 mg, 34%). LC-MS: m/z 403.0[ m+h ] +, (esi+), rt=1.29 LCMS method 1.

Intermediate 4

Step 4:3- (4-fluoro-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methylpyridazine-4-carboxylate (42%, 1.153g,1.20 mmol), copper iodide (0.35 g,1.81 mmol) and tetrabutylammonium iodide (0.18 g, 0.480 mmol) in DMF (6.4023 mL) was added methyl difluoro (fluorosulfonyl) acetate (1.16 g,6.02 mmol) and stirred at 70℃for 2h. The reaction was cooled to room temperature, filtered and washed with EtOAc (2×20 mL). The filtrate was washed with brine (50 mL) and over MgSO ₄ Drying, filtration and concentration under reduced pressure gave a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 20% etoac/heptane afforded the title compound (97.0%) as a pale yellow oil (425 mg, 99%). LC-MS: m/z 345.0[ M+H ]]+, (esi+), rt=1.33 LCMS method 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.31-7.23(m,2H),7.14(td,J＝8.6,3.2Hz,1H),4.02(s,3H),2.48-2.44(m,3H),2.09(s,3H)。

Intermediate 5

Step 5:3- (4-fluoro-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid: to a mixture of 3- (4-fluoro-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (97%, 425mg,1.20 mmol) in THF (4.5806 mL) was added water (0.9161 mL) and lithium hydroxide (149 mg,5.99 mmol) and the mixture was stirred at room temperature for 16h. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (407 mg, 99%) as a pale yellow solid.

Intermediates 6 to 15 listed in table 1 were prepared by a similar procedure as described for step 1 of scheme 4 using the appropriate starting materials.

TABLE 1

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Intermediates 16 to 24 listed in table 2 were prepared by a similar procedure as described for step 2 of scheme 4 using the appropriate starting materials.

Table 2.

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Intermediates 25 to 35 listed in table 3 were prepared by a similar procedure as described for step 3 of scheme 4 using the appropriate starting materials.

Table 3.

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Intermediates 36 to 46 listed in table 4 were prepared by a similar procedure as described for step 4 of scheme 4 using the appropriate starting materials.

Table 4.

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Intermediates 47 to 56 listed in table 5 were prepared by a similar procedure as described for step 5 of scheme 4 using the appropriate starting materials.

Table 5.

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Intermediate 57

4- (cyclobutoxy) -2, 3-difluoro-phenol

Reagents and conditions: a) Tosyl chloride, TEA, DCM, room temperature, 18h b) 4-bromo-2, 3-difluorophenol, K ₂ CO ₃ DMF,90 ℃,4h c) KOH, (1{E, 4{E }) -1, 5-diphenylpenta-1, 4-dien-3-one; palladium, di-tert-butyl l [3,4,5, 6-tetramethyl-2 ',4',6' -tri (propan-2-yl) biphenyl-2-yl]Phosphine, 1:1, 4-dioxane/water, 100 ℃,18h

Step 1: 4-methylbenzenesulfonic acid cyclobutyl ester: to a solution of cyclobutanol (0.22 mL,2.77 mmol) in DCM (6 mL) under nitrogen was added 4-toluenesulfonyl chloride (635 mg,3.33 mmol) followed by triethylamine (0.46 mL,3.33 mmol). The mixture was stirred at room temperature for 18h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2×5 mL). The organic phase was dried (MgSO ₄ ) Filtered and concentrated to give a clear oil. By FCC (Biotage isolera, siO ₂ Gradient elution, 0 to 20% EtOAc/heptane) afforded 4-methylbenzenesulfonic acid cyclobutyl ester (97%) as a clear oil (362 mg,1.599mmol, 58%). m/z:227.1[ M+H ]] ⁺ (esi+), rt= 0.91METCR1704 (IPC 2 min upc gradient method).

Step 2: 1-bromo-4- (cyclobutoxy) -2, 3-difluoro-benzene: to a solution of 4-bromo-2, 3-difluorophenol (1.40 g,6.70 mmol) and 4-methylbenzenesulfonic acid cyclobutyl ester (1.82 g,8.04 mmol) in DMF (10 mL) was added dipotassium carbonate (1.39 g,10.0 mmol). The mixture was heated at 90℃for 4h. The mixture was cooled to room temperature, then diluted with ethyl acetate (60 mL) and washed with water (3×30 mL) and brine (30 mL). The organics were dried (MgSO ₄ ) Filtered and concentrated to give an orange oil. By FCC (Biotage isolera, siO ₂ Gradient elution, 0 to 10% etoac/heptane) afforded 1-bromo-4- (cyclobutoxy) -2, 3-difluoro-benzene (76%) as a clear oil (0.983 g,3.737mmol, 43%). LC-MS: m/z 263.2[ M] ⁺ (esi+), rt= 1.10METCR1704 (IPC 2 min upc gradient method).

Step 3:4- (cyclobutoxy) -2, 3-difluoro-phenol: 1-bromo-4- (cyclo)A mixture of butoxy) -2, 3-difluoro-benzene (640 mg,3.73mmol and potassium hydroxide (418 mg,7.45 mmol) in 1, 4-dioxane (5 mL) and water (5 mL) was degassed by nitrogen bubbling for 10min followed by the addition of di-tert-butyl [3,4,5, 6-tetramethyl-2 ',4',6' -tri (propan-2-yl) biphenyl-2-yl ]Phosphine (143 mg,0.298 mmol) and (1{E, 4{E) -1, 5-diphenylpentan-1, 4-dien-3-one; palladium (68 mg,0.0745 mmol) and the reaction was stirred at 100℃for 18h. The pH was adjusted to about 3 with 1M HCl and the mixture was extracted with ethyl acetate (3X 8 mL). The combined organics were dried (MgSO 4), filtered and concentrated to a brown oil. By FCC (Biotage isolera, siO ₂ Gradient elution, 0 to 5% etoac/heptane) afforded 4- (cyclobutoxy) -2, 3-difluoro-phenol (90%) as a pale orange solid (62 mg,3.107mmol, 75%). LC-MS: m/z 199.1[ M-H ]] ^- (ESI-), rt= 0.82METCR1704 (IPC 2 min upc gradient method).

Intermediate 58 and intermediate 59

(S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate intermediate 58]And (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate [ intermediate 59 ]]。

Reagents and conditions: NH (NH) ₄ (OAc)、PhI(OAc) ₂ EtOH, room temperature, 16h; b) t-BuOK, (Boc) ₂ O, t-BuOH, refluxing for 10h; c) Pd (OH) ₂ 、H ₂ MeOH, room temperature, 2h; d) SFC purification

Step 1: imino (methyl) (3-nitrophenyl) -lambda ⁶ Thioketone: to a mixture of methyl (3-nitrophenyl) sulfane (8.2 g,48.5 mmol) and ammonium acetate (5.6 g,72.7 mmol) in EtOH (120 mL) was added PhI (OAc) in one portion ₂ (31.2 g,97 mmol). The reaction mixture was stirred at room temperature under atmospheric air for 16h. The mixture was concentrated directly to give a residue which was purified by silica gel chromatography column (PE: ea=5:1 to 1:3) to give imino (methyl) (3-nitrophenyl) - λ as a white solid ⁶ Thioketone(7.0 g, 72%). MS (esi+): m/z Experimental value 201.03[ M+H ]] ⁺ 。

Step 2: (methyl (3-nitrophenyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate: at N ₂ Protected by imino (methyl) (3-nitrophenyl) -lambda ⁶ To a solution of thione (3.5 g,17.5 mmol) in t-BuOH (200 mL) cooled with an ice-water bath was added t-BuOK (3.9 g,35.0 mmol). Subsequently, slow addition (Boc) ₂ O (7.6 g,35.0 mmol) followed by refluxing the reaction mixture for 10h. The reaction mixture was saturated with NH ₄ The Cl solution (200 mL) was quenched and extracted with EA (200 mL. Times.2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Drying and concentration gave a residue which was purified by silica gel chromatography column (PE: ea=5:1 to 1:1) to give (methyl (3-nitrophenyl) (oxo) - λ as a yellow solid ⁶ Tert-butyl (sulfoalkyl) carbamate (1.8 g, 34%). LC-MS (esi+): m/z 301.09[ M+H ]] ⁺ 。

Step 3: (3-aminophenyl) (imino) (methyl) -lambda ⁶ Thioketone: to (methyl (3-nitrophenyl) (oxo) -lambda ⁶ To a solution of tert-butyl (sulfoalkyl) carbamate (1.8 g,6 mmol) in MeOH (30 mL) was added Pd (OH) ₂ (300 mg) and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue, which was redissolved in EA (30 mL) and the resulting solution was filtered again through celite and washed with EA (100 mL). The filtrate was concentrated to give ((3-aminophenyl) (methyl) (oxo) -lambda as an off-white solid ⁶ Tert-butyl (alkylene) carbamate (1.4 g, 86%). MS (esi+): experimental value of m/z 271.10[ M+H ]] ⁺ 。

Step 4: SFC separation: the racemic product was separated using chiral high performance liquid chromatography, wherein chiral separation conditions: column: daicel CHIRALPAK IG,250mm×20mm I.D.,5 μm; mobile phase a: CO ₂ /MeOH[0.2％NH ₃ (7M MeOH solution)]=70/30; flow rate: 60g/min;214nm; temperature: 35 ℃. The first eluting isomer (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate intermediate 58]。 ¹ H NMR(DMSO-d ₆ ) Delta 7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s.9H), and the second eluting isomer (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate [ intermediate 59 ]]。 ¹ H NMR(DMSO-d ₆ )δ7.26(t,1H),7.08(s,1H),6.97(d,1H),6.83(d,1H),5.71(s,2H),3.28(s,3H),1.27(s.9H)。

Example 7

Compound 1:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 3- (methylsulfonyl) aniline, 50% propylphosphonic anhydride solution/EtOAc, N-Diisopropylethylamine (DIEA), DCM, room temperature.

A mixture of N, N-Diisopropylethylamine (DIEA) (0.16 mL, 0.258 mmol), 3- (4-fluoro-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.100 g,0.303 mmol) and 3- (methylsulfonyl) aniline (0.062 g, 0.803 mmol) was dissolved in DCM (4.8 mL) under nitrogen at room temperature. To the above mixture was added a 50% solution of propylphosphonic anhydride/EtOAc (50%, 0.36mL,0.606 mmol) in one portion. The reaction mixture was stirred at room temperature for 4h. The reaction was then stirred at 55℃for 16h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude residue. Purification by preparative LC method P1 gave the title compound as a white solid (0.025 g, 17%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.39(s,1H),8.38(t,J＝1.8Hz,1H),7.90(ddd,J＝7.9,2.0,1.2Hz,1H),7.78-7.73(m,1H),7.70(t,J＝7.9Hz,1H),7.29(dd,J＝8.9,5.0Hz,1H),7.24(dd,J＝9.4,3.1Hz,1H),7.14(td,J＝8.5,3.1Hz,1H),3.24(s,3H),2.54-2.51(m,3H),2.12(s,3H)。LC-MS：m/z 484.0[M+H] ⁺ (esi+), rt=4.24 LCMS method 5.

Example 8

Compound 2: 5-methyl-N- (3-methylsulfonylphenyl) -3- [ 2-methyl-4- (trifluoromethyl) phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a method similar to that described for compound 1 using 5-methyl-3- (2-methyl-4- (trifluoromethyl) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid and 3- (methylsulfonyl) aniline. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.42(s,1H),8.37(t,J＝1.8Hz,1H),7.93-7.87(m,1H),7.80-7.66(m,4H),7.51(d,J＝8.4Hz,1H),3.24(s,3H),2.56-2.53(m,3H),2.21(s,3H)。m/z：534.1[M+H] ⁺ (esi+), rt=3.81 LCMS method 4

Example 9

Compound 3: 5-methyl-3- (2-methyl-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

A mixture of 3- (methylsulfonyl) aniline (41 mg,0.242 mmol) using 5-methyl-3- (2-methyl-4- (trifluoromethoxy) phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (85 mg,0.202 mmol) was dissolved in DMF (0.5085 mL) under nitrogen at room temperature. N-ethyl-N-isopropyl-propan-2-amine (0.070 mL,0.403 mmol) was then added followed by N- [ (dimethylamino) (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]N-methyl ammonium hexafluorophosphate (77 mg,0.202 mmol). The reaction mixture was stirred at room temperature for 1h. The reaction was diluted with brine (10 mL) and extracted with EtOAc (2X 10 mL). The organics were washed with 1M HCl (10 mL) over MgSO ₄ Drying, filtration and concentration under reduced pressure gave a crude residue which was purified using preparation method 1 to give 5-methyl-3- (2-methyl-4- (trifluoromethoxy) phenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (51 mg, 46%) as an off-white solid. ¹ H NMR(500MHz,CD ₃ OD)δ8.41(t,J＝1.9Hz,1H),7.97(ddd,J＝8.1,2.1,1.1Hz,1H),7.79(ddd,J＝7.8,1.7,1.0Hz,1H),7.68(t,J＝8.0Hz,1H),7.32(d,J＝8.9Hz,1H),7.29-7.25(m,1H),7.21(dd,J＝8.8,2.7Hz,1H),3.15(s,3H),2.62-2.57(m,3H),2.21(s,3H)。m/z：550.5[M+H] ⁺ (esi+), rt=4.50 LCMS method 5.

Example 10

Compound 4:3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 3-methanesulfonylaniline, HATU, DIEA, DMF, room temperature

To a mixture of 3- (4-cyano-2-methoxyphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.060, 0.170 mmol), 3-methanesulfonylaniline (0.029 g,0.170 mmol), HATU (0.097 g,0.255 mmol) in DMF (3 mL) was added DIEA (0.089 mL,0.510 mmol) at 25 ℃ and stirring was continued for an additional 16h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2X 30 mL). The combined EtOAc layers were washed with 1M LiCl (10 mL) followed by brine (20 mL). EtOAc layer over Na ₂ SO ₄ Dried, filtered, and the solvent evaporated. SiO of the crude product on a gradient with 0 to 10% EtOAc/DCM ₂ Chromatography thereon gave 3- (4-cyano-2-methoxyphenoxy) -N- (3-methanesulfonylphenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide (0.028 g, 33%). ¹ H NMR(300MHz,CDCl ₃ )δ8.52(s,1H),8.15-7.97(m,2H),7.77(dt,J＝7.9,1.3Hz,1H),7.63(t,J＝8.0Hz,1H),7.41(d,J＝1.5Hz,2H),7.30(s,1H),3.89(s,3H),3.09(s,3H),2.67(q,J＝1.5Hz,3H)。LC-MS：m/z 505.3[M-H] ⁺

Compounds 5 to 7 listed in table 6 were prepared by similar procedure as described for compound 4.

Table 6.

Example 11

Compound 8:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: DIEA, propylphosphonic anhydride solution/EtOAc (50%; v/v), DMAP, 3- (methylthio) aniline, DCM,55℃for 16h.

To a mixture of 3- (4-fluoro-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (100 mg,0.303 mmol) in DCM (1.9151 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.12 mL,0.666 mmol) and N, N-dimethylpyridin-4-amine (7.4 mg,0.0606 mmol) at room temperature followed by 50% propylphosphonic anhydride solution/EtOAc (50%, 0.36mL,0.606 mmol). The mixture was stirred at room temperature for 15min. 3- (methylthio) aniline (51 mg,0.363 mmol) was added to the reaction. The reaction mixture was stirred at room temperature for 10min and then at 55 ℃ for 16h. Volatiles were removed in vacuo. Purification by silica gel chromatography eluting with a gradient of 0% to 100% EtOAC/heptane followed by a gradient of 0-60% meoh/EtOAC afforded 3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (methylsulfanyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (43.0%) as a yellow solid (110 mg, 35%). LC-MS: m/z 452.6[ M+H ]] ⁺ (esi+), rt=4.81 LCMS method 5.

Compounds 9 to 13 listed in table 7 were prepared by a similar procedure as described for compound 8.

Table 7.

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Example 12

Compound 14:3- (4-cyano-2-methylphenoxy) -5-methyl-N- [3- (methylsulfanyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: HATU, 3- (methylthio) aniline, DIEA, DMF, room temperature, 16h.

To a mixture of 3- (4-cyano-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.300 g, 0.89mmol), 3- (methylthio) aniline (0.124 g,0.890 mmol) and HATU (0.676 g,1.78 mmol) in DMF (10 mL) was added DIEA (0.0345 g,2.67 mmol) at room temperature. The resulting mixture was stirred for an additional 16h, water (10 mL) was added at the end of this period and extracted with EtOAc (2×40 mL). The combined EtOAc layers were washed with 1M LiCl (20 mL) followed by brine (30 mL). EtOAc layer over Na ₂ SO ₄ Dried, filtered, and the solvent evaporated. The crude material was purified on SiO with a gradient of 0 to 50% EtOAc in hexane ₂ Chromatographic analysis of the mixture to obtain 3- (4-cyano-2-methylphenoxy) -5-methyl-N- [3- (methylthio) phenyl]-6- (trifluoromethyl) pyridazine-4-carboxamide (0.165 g, 40.46%). ¹ H NMR(300MHz,CDCl3)δ7.72-7.49(m,3H),7.37-7.21(m,4H),7.19-7.06(m,1H),2.63(q,J＝1.5Hz,3H),2.52(s,3H),2.23(s,3H)。LC-MS：m/z 457.3[M-H] ⁺ 。

Compounds 15 to 19 listed in table 8 were prepared by a similar procedure as described for compound 14.

Table 8.

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Example 13

Compound 20:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Ammonium carbonate, (diacetoxyiodo) benzene, meOH, room temperature, 24h

Solution 3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (43%) (0.090 g,0.0857 mmol) was dissolved in methanol (0.3518 mL) and treated with ammonium carbonate (0.012 g,0.13 mmol) and (diacetoxyiodo) benzene (0.064 mg, 0.197mmol), each added in one portion. The resulting mixture was stirred at room temperature for 24h. The solvent was removed in vacuo. Purification by chromatography gave the title compound (0.032 g, 75%) as a pale brown solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.35(s,1H),8.36(t,J＝1.9Hz,1H),7.90-7.84(m,1H),7.76-7.71(m,1H),7.64(t,J＝7.9Hz,1H),7.29(dd,J＝8.9,5.0Hz,1H),7.24(dd,J＝9.3,3.0Hz,1H),7.14(td,J＝8.5,3.1Hz,1H),4.25(s,1H),3.07(s,3H),2.52(s,3H),2.12(s,3H)。LC-MS：m/z 482.9[M+H] ⁺ (esi+), rt=3.83 LCMS method 5.

Compounds 21 to 29 listed in table 9 were prepared by similar procedure as described for compound 20.

Table 9.

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Example 14

Compounds 30 and 31: chiral separation of 3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Chiral purification of 3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (compound 20) was performed using the following: preparative chiral HPLC on Chiralpak AD-H (20X 250 m) 5 μm eluting with a mixture of heptane and ethanol (70:30) at a flow rate of 18mL/min. The fractions containing the product were evaporated and separated as viscous oils, which were redissolved in 1:1mecn in water (1 mL) and lyophilized to give the first eluting isomer (compound 30) as an off-white solid (39 mg, 32%). LC-MS: m/z:483.2[ M+H ] ] ⁺ (esi+), rt=3.15 LCMS method 6. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.31 (s, 1H), 8.38-8.33 (m, 1H), 7.90-7.83 (m, 1H), 7.77-7.70 (m, 1H), 7.64 (t, j=7.9 hz, 1H), 7.29 (dd, j=8.8, 5.0hz, 1H), 7.24 (dd, j=9.4, 3.0hz, 1H), 7.14 (td, j=8.7, 3.2hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.52-2.52 (m, 3H), 2.12 (s, 3H). The analysis method comprises the following steps: mobile phase 70:30 heptane ethanol; column Chiralpak AD-H, 4.6X250 mm,5 μm; flow rate 1mL/min and second eluting isomer (compound 31) as an off-white solid (0.038 mg, 32%).

¹ H NMR(400MHz,CD ₃ OD)δ8.45(t,J＝1.9Hz,1H),7.96(ddd,J＝8.1,2.1,1.0Hz,1H),7.84(ddd,J＝7.9,1.8,1.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.21(dd,J＝8.8,4.9Hz,1H),7.09(dd,J＝9.1,3.1Hz,1H),7.01(td,J＝8.5,3.1Hz,1H),3.17(s,3H),2.62-2.55(m,3H),2.17(s,3H)。m/z：483.5[M+H] ⁺ (esi+), rt=3.82 LCMS method 5.

Example 15

Compounds 32 and 33: chiral separation of 5-methyl-3- (2-methyl-4- (trifluoromethoxy) phenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

5-methyl-3- (2-methyl-4- (trifluoromethoxy) phenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide was prepared by a similar procedure to that described for compound 20 and purified using the following: preparative chiral HPLC on Chiralpak AD-H (20X 250 m) 5 μm eluting with a mixture of heptane and ethanol (70:30) at a flow rate of 18mL/min. The fractions containing the product were evaporated and separated as viscous oils, and these fractions were redissolved in 1:1mecn in water (1 mL) and lyophilized to give the first eluting isomer (compound 32) as a beige solid (63 mg, 37%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(t,J＝1.8Hz,1H),7.90-7.83(m,1H),7.73(d,J＝7.7Hz,1H),7.64(t,J＝8.0Hz,1H),7.44-7.38(m,2H),7.35-7.30(m,1H),4.25(s,1H),3.07(d,J＝0.8Hz,3H),2.54-2.52(m,3H),2.16(s,3H)。m/z：549.2[M+H]+, (esi+), rt=3.60 LCMS method 6 and the second eluting isomer (compound 33) as a beige solid (54 mg, 31%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(t,J＝1.9Hz,1H),7.89-7.83(m,1H),7.73(d,J＝7.8Hz,1H),7.63(t,J＝7.8Hz,1H),7.45-7.37(m,2H),7.35-7.29(m,1H),4.25(s,1H),3.10-3.01(m,3H),2.53-2.52(m,3H),2.16(s,3H)。m/z：549.2[M+H] ⁺ (esi+), rt=3.60 LCMS method 6.

Example 16

Compounds 34 and 35: chiral separation of 5-methyl-3- (2-methyl-4- (trifluoromethyl) phenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

5-methyl-3- (2-methyl-4- (trifluoromethyl) phenoxy) -N- (3- (S-methanesulfonyl) sulfinyl) Phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide was prepared by a similar procedure to that described for compound 20 and purified using the following: preparative chiral HPLC on Chiralpak AD-H (20X 250 m) 10 μm, eluting with a mixture of Chiralpak AD-H (20X 250 m) 5 μm with a mixture of heptane: ethanol (85:15), flow rate 18mL/min. The eluate containing the product was evaporated to give the first eluted isomer (compound 34) (99 mg, 29%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(t,J＝1.8Hz,1H),7.91-7.84(m,1H),7.81-7.77(m,1H),7.76-7.68(m,2H),7.64(t,J＝7.9Hz,1H),7.51(d,J＝8.4Hz,1H),4.25(s,1H),3.10-3.04(m,3H),2.55-2.53(m,3H),2.21(s,3H)。LC-MS：m/z 533.6[M+H] ⁺ (esi+), rt=4.15 LCMS method 5 and the second eluting isomer (compound 35) as a white solid (92 mg, 27%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(t,J＝1.8Hz,1H),7.90-7.85(m,1H),7.81-7.77(m,1H),7.76-7.67(m,2H),7.64(t,J＝7.9Hz,1H),7.51(d,J＝8.5Hz,1H),4.25(s,1H),3.11-3.05(m,3H),2.55-2.52(m,3H),2.21(s,3H)。LC-MS：m/z：533.6[M+H] ⁺ (esi+), rt=4.14 LCMS method 5.

Example 17

Compounds 1401 to 1429 listed in table 10 were prepared by similar procedure as described for compound 14.

Table 10.

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Example 18

Compound 1430:6- (3-Fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N-pyridazin-4-yl-pyridazin-4-carboxamide

Reagents and conditions: a) (4R) -4-hydroxy-L-proline, 3-fluoroazetidine hydrochloride, tripotassium phosphate, copper iodide, CH ₃ CN、DMSO，50℃，104h；b)LiOH、THF:H ₂ O (7:1, v/v), room temperature, 2h; c) HATU, pyridazin-4-amine, DIPEA, DMF, room temperature, 2h.

Step 1:6- (3-Fluoronitrogen)Azetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid methyl ester: (4R) -4-hydroxy-L-proline (16 mg,0.124 mmol) was added to N ₂ Degassed methyl 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylate (250 mg,0.62 mmol), 3-fluoroazetidine hydrochloride (139 mg,1.24 mmol), copper iodide (12 mg,0.0622 mmol) and tripotassium phosphate (390 mg,1.86 mmol) were mixed in anhydrous acetonitrile (2.5 mL) and anhydrous DMSO (2 mL) and the reaction stirred at 50 ℃ for 80h. Additional reagents (4R) -4-hydroxy-L-proline (16 mg,0.124 mmol), 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (250 mg,0.62 mmol), 3-fluoroazetidine hydrochloride (1:1) (139 mg,1.24 mmol), copper iodide (1+) (12 mg,0.0622 mmol) and tripotassium phosphate (390 mg,1.86 mmol) were added and the reaction stirred at 70℃for a further 24h. The reaction was diluted in EtOAc (about 60 mL) and washed successively with 1M aqueous HCl, water and brine, dried over sodium sulfate and concentrated to dryness in vacuo to give the crude title compound 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid methyl ester (699 mg, 100%) as brown gum, which was used as such in the next step without further analysis or purification assuming a 100% molar yield. m/z:350[ M+H ] ] ⁺ (esi+), rt= 0.89min METCR1704 (IPC 2 min upc gradient method).

Step 2: 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid: lithium hydroxide (93 mg,3.73 mmol) was added to a mixture of methyl 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylate (217 mg,0.622 mmol) in THF (4.2 mL) and water (0.6 mL) and the mixture was stirred at room temperature for 16h. The reaction was stirred for a further 24h, followed by a further 8h (total 56 h) at 40 ℃. The reaction was diluted with water (20 mL) and the pH was adjusted to about 1-2 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 20 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to afford the title compound 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid (59.0%) as a brown solid (353 mg, 100%) which was used without further analysis or purificationIn the next step. LC-MS: m/z 336[ M+H ]] ⁺ (esi+), rt= 0.46min METCR1704 (IPC 2 min upc gradient method).

Step 3:6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N-pyridazin-4-yl-pyridazin-4-carboxamide: HATU (130 mg, 0.348 mmol) was added to a mixture of 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid (104 mg,0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 ul,0.684 mmol) in DMF (2 mL) at room temperature and the reaction was stirred at room temperature for 5min, followed by pyridazin-4-amine (44 mg, 0.463 mmol) and the reaction was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3×50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to afford the crude product. Purification by high pH preparative HPLC (early method) gave the title compound 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N-pyridazin-4-yl-pyridazine-4-carboxamide (20 mg,0.0478mmol, 15%) as an off-white solid. ¹ H NMR(400MHz,MeOH-d ₄ )δ9.31(d,J＝1.9Hz,1H),9.08(d,J＝5.9Hz,1H),8.19(dd,J＝5.9,2.7Hz,1H),7.11(dd,J＝8.9,4.9Hz,1H),7.00(dd,J＝9.2,3.0Hz,1H),6.97-6.88(m,1H),5.43(dm,J＝57.8,9.4,5.9,3.5Hz,1H),4.55-4.41(m,2H),4.31-4.18(m,2H),2.30(s,3H),2.15(s,3H)。m/z：413.3[M+H] ⁺ (esi+), rt=2.45 LCMS method 6

Example 19

Compound 1431:6- (3-Fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

Reagents and conditions: a) HATU, 3- (methylthio) aniline, DIPEA, DMF, room temperature, 2h. b) PIDA, (NH 4) ₂ CO ₃ MeOH, room temperature, 3 days.

Step 1:6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide: HATU (130 mg, 0.348 mmol) was added to a mixture of 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-pyridazine-4-carboxylic acid (104 mg,0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 ul,0.684 mmol) in DMF (2 mL) at room temperature and the reaction was stirred at room temperature for 5min, followed by 3- (methylthio) aniline (57 ul, 0.463 mmol) and the reaction was stirred at room temperature for 2h.

The reaction mixture was diluted with EtOAc (about 50 mL) and washed with water (3×about 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purification by FCC (Biotage Isolera, siO2, gradient elution 10-50% etoac in heptane) afforded the title compound 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (90.0%) as a yellow gum (30 mg,0.0591mmol, 19%). LC-MS: m/z:457[ M+H ] ] ⁺ (esi+), rt= 0.95min METCR1704 (IPC 2 min upc gradient method)

Step 2:6- (3-Fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: to a solution of 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (30 mg,0.0657 mmol) in methanol (1 mL) was added phenyliodiammonium diacetate (PIDA) (49 mg,0.151 mmol) and diammonium carbonate (10 mg,0.105 mmol) at room temperature and the reaction was stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness in vacuo to give the crude product. The residue was purified by low pH preparative HPLC (early method). The product-containing fractions were combined and the solvent removed in vacuo to give the title compound 6- (3-fluoroazetidin-1-yl) -3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl as an off-white solid]Pyridazine-4-carboxamide (100.0%) (12 mg,0.0246mmol, 37%). ¹ H NMR(400MHz,CD ₃ OD)δ8.43(t,J＝1.9Hz,1H),7.99-7.90(m,1H),7.86-7.76(m,1H),7.64(t,J＝8.0Hz,1H),7.11(dd,J＝8.9,4.9Hz,1H),7.01(dd,J＝9.1,3.0Hz,1H),6.99-6.93(m,1H),5.52-5.34(dm,J＝57.8,Hz,1H),4.48m,2H),4.24-4.19(m,2H),3.17(s,3H),2.30(s,3H),2.16(s,3H)。m/z：488.3[M+H] ⁺ (esi+), rt=2.65 min LCMS method 6.

Example 20

Compound 1432: 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3 (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

Reagents and conditions: a) LiOH, THF, water, room temperature, 40h. b) 3- (methylthio) aniline, HATU, DIPEA, DMF, room temperature, 40h. b) HATU, 3- (methylthio) aniline, DIPEA, DMF, room temperature, 16h. c) Pd (OAc) ₂ 、DPEphos、K ₄ [Fe(CN) ₆ ]·3H ₂ O、Na ₂ CO ₃ 1, 4-dioxane, water, NMP,70 ℃ for 21h. d) PIDA, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 16h.

Step 1:3- (2-fluoro-4-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid: lithium hydroxide (126 mg,5.05 mmol) was added to a mixture of 3- (2-fluoro-4-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (677 mg,1.68 mmol) in THF (11 mL) and water (1.7 mL) and the mixture was stirred at room temperature for 40h. The reaction was diluted with water (20 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the title compound 3- (2-fluoro-4-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid (611 mg,1.59mmol, 94%) as a pale yellow solid, which was used as such in the next step. LC-MS: m/z:389[ M+H ]] ⁺ (esi+), rt= 0.61METCR1410 typically 2min

Step 2:3- [2, 6-difluoro-4- (trifluoromethoxy) phenoxy]-5-methyl-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: HATU (665 mg,1.75 mmol) was added to a mixture of 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid (617 mg,1.59 mmol) and N-ethyl-N-isopropyl-propan-2-amine (555 ul,3.18 mmol) in DMF (11.5 mL) at room temperature and the reaction was stirred at room temperature for 5min, followed by addition 3- (methylthio) aniline (235 uL,1.91 mmol) was added and the reaction stirred at room temperature for 16h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3×50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. By FCC (Biotage Isolera, siO ₂ Gradient elution 10-30% EtOAc in heptane) afforded the title compound 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (682 mg, 68%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.63(s,1H),7.37-7.26(m,3H),7.19-7.04(m,2H),6.94(dd,J＝8.8,3.0Hz,1H),6.86(td,J＝8.3,3.1Hz,1H),2.69-2.52(m,3H),2.50(s,3H),2.15(d,J＝4.6Hz,3H)。m/z：510[M+H] ⁺ (esi+), rt= 1.02min METCR1410 typically 2min

Step 3: 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide: palladium acetate (4.4 mg,0.0196 mmol) was added to 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (50 mg,0.0982 mmol), potassium (II) hexacyanoferrite trihydrate (36 mg,0.0982 mmol), sodium carbonate (21 mg,0.196 mmol) and [2- (2-diphenylphosphinophenoxy) phenyl ]]Stirred and N-treated diphenylphosphine (21 mg,0.0393 mmol) in 1, 4-dioxane (0.28 mL) and water (0.28 mL) ₂ In the degassed solution. The reaction mixture was heated in a pressure flask at 70 ℃ for 1h. The reaction appeared heterogeneous, so NMP (0.25 mL) was added and the reaction stirred overnight (20 h) at 70 ℃. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×20 mL) and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product (about 130 mg). By FCC (Biotage Isolera, siO ₂ Gradient elution 0-50% etoac in heptane) afforded the title compound 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (99.0%) as a yellow solid (30 mg,0.0727mmol, 74%). LC-MS: m/z:409[ M+H ]] ⁺ (esi+), rt= 0.99min METCR1410 typically 2min

Step 4: 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl- [3 (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: at room temperatureTo a solution of 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (30 mg,0.0734 mmol) in methanol (1 mL) was added phenyliodiammonium diacetate (PIDA) (54 mg,0.169 mmol) and diammonium carbonate (10 mg,0.110 mmol) and the reaction was stirred at room temperature for 16h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. Purification by FCC (Biotage isolera, gradient elution 0-100% EtOAc in heptane) afforded the title compound less than the desired purity%, so the product was further purified by low pH preparative HPLC (early method). The eluted products were combined and the solvent was removed by freeze-drying overnight in vacuo to give the title compound 6-cyano-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl as an off-white solid ]Pyridazine-4-carboxamide (99.0%) (6.1 mg,0.0137mmol, 19%). ¹ H NMR(400MHz,CD ₃ OD)δ8.44(t,J＝1.9Hz,1H),7.99-7.92(m,1H),7.87-7.81(m,1H),7.67(t,J＝8.0Hz,1H),7.21(dd,J＝8.9,4.9Hz,1H),7.09(dd,J＝9.0,3.0Hz,1H),7.06-6.97(m,1H),3.17(s,3H),2.62(s,3H),2.16(s,3H)。LC-MS：m/z 440[M+H] ⁺ (esi+), rt=2.83 min MET-uPLC-AB-101 (7 min, low pH).

Example 21

Compound 1433: 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [ (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

Reagents and conditions: a) Pd (PPh) ₃ ) ₄ Cyclopropyl SnBu ₃ Toluene, 70℃for 16h. b) PIDA, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 4 days.

Step 1: 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide: palladium-triphenylphosphine (1:4) (18 mg,0.0159 mmol) was added to 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (81 mg, 0.1599 mmol) and tributyl (cyclopropyl) stannane in anhydrous toluene (0.5 mL) under stirring andwarp N ₂ The degassed solution was stirred in a pressure flask at 70 ℃ for 16h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. By FCC (Biotage Isolera, siO ₂ Gradient elution 0-30% EtOAc in heptane) afforded the title compound 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (66.0%) as a pale yellow oil (98 mg,0.153mmol, 96%). LC-MS: m/z 424[ M+H ] ] ⁺ (esi+), rt= 1.00min METCR1410 typically 2min

Step 2: 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [ (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: to a solution of 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (66%, 98mg,0.153 mmol) in methanol (2.2 mL) was added phenyliodiammonium diacetate (PIDA) (226 mg, 0.803 mmol) and diammonium carbonate (43 mg,0.458 mmol) at room temperature and the reaction was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (Biotage Isolera SiO ₂ Gradient elution (0-100% EtOAc in heptane) purification. The product was less pure than desired, and therefore purified by low pH preparative HPLC (early method). The eluted products were combined and the solvent was removed by freeze-drying overnight in vacuo to give the title compound 6-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl as an off-white solid]Pyridazine-4-carboxamide (100.0%) (22 mg,0.0477mmol, 31%). ¹ H NMR(500MHz,CD ₃ OD)δ8.45(t,J＝1.9Hz,1H),7.99-7.92(m,1H),7.87-7.78(m,1H),7.65(t,J＝8.0Hz,1H),7.13(dd,J＝8.9,4.9Hz,1H),7.03(dd,J＝9.1,3.0Hz,1H),6.95(td,J＝8.5,3.1Hz,1H),3.17(s,3H),2.54(s,3H),2.24(p,J＝6.6Hz,1H),2.15(s,3H),1.09(d,J＝6.4Hz,4H)。LC-MS：m/z 455[M+H] ⁺ (esi+), rt=2.63 min MET-uPLC-AB-101 (7 min, low pH).

Example 22

Compound 1434:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (prop-1-yn-1-yl) pyridazine-4-carboxamide

Reagents and conditions: a) PIDA, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 5h. b) Prop-1-yne (1M/THF), pdCl ₂ (dppf)、CuI、THF，70℃

Step 1:3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: to a solution of 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (534 mg,1.05 mmol) in methanol (15 mL) was added phenyliodiammonium diacetate (PIDA) (780 mg,2.42 mmol) and diammonium carbonate (158 mg,1.68 mmol) at room temperature and the reaction was stirred at room temperature for 5h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. Purification by FCC (Biotage Isolera, gradient elution 10-100% EtOAc in heptane) afforded the title compound 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl ] as a pale yellow solid]Pyridazine-4-carboxamide (89.0%) (520 mg,0.856mmol, 81%). LC-MS: m/z 541[ M+H ]] ⁺ (esi+), rt= 0.75METCR1410 typically 2min

Step 2:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (prop-1-yn-1-yl) pyridazine-4-carboxamide: 1M solution of prop-1-yne (1M/THF) (925 uL,0.925 mmol) was added to 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl ]Pyridazine-4-carboxamide (50 mg,0.0925 mmol), copper iodide (1+) (21 mg,0.111 mmol) and 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (1:1) (6.8 mg, 9.25. Mu. Mol) in anhydrous THF (0.5 mL) were stirred in a N2 degassed mixture and the reaction mixture was stirred in a pressure flask at room temperature for 20h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. By FCC (BiotageIsolera, siO) ₂ Gradient elution 0-30% etoac in heptane) to afford the title compound, which is less than the particular purity desired, thus purifying the product by low pH preparative HPLC (standard procedure). The product-containing fractions were combined and the solvent removed in vacuo to give the title compound 3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methyl) as an off-white solidSulfoimidoyl) phenyl]-6-prop-1-ynyl-pyridazine-4-carboxamide (100.0%) (15 mg,0.0340mmol, 37%). ¹ H NMR(400MHz,CD ₃ OD)δ8.44(t,J＝1.9Hz,1H),7.99-7.92(m,1H),7.85-7.78(m,1H),7.65(t,J＝8.0Hz,1H),7.17(dd,J＝8.9,4.9Hz,1H),7.05(dd,J＝9.1,3.0Hz,1H),7.02-6.94(m,1H),3.17(s,3H),2.51(s,3H),2.19(s,3H),2.16(s,3H)。LC-MS：m/z 453.3[M+H] ⁺ (esi+), rt=2.78 MET-uPLC-AB-107 (7 min, high pH).

EXAMPLE 23

Compound 1435:3- (3, 4-difluoro-2-methoxyphenoxy) -5, 6-dimethyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide

Reagents and conditions: a) 3-chloro-5, 6-dimethylpyridazine-4-carbonitrile, K ₂ CO ₃ MeCN, 70 ℃,18, H b) barium hydroxide, H ₂ O, 80 ℃,17h c) 1-bromo-3- (methylthio) benzene, cesium carbonate, pd ₂ (dba) ₃ XantPhos, 1-4-dioxane, 100 ℃,4h d) PIDA, diammonium carbonate, meOH, room temperature, 17h

Step 1:3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carbonitrile

A mixture of 3, 4-difluoro-2-methoxy-phenol (1.00 g,6.25 mmol), 3-chloro-5, 6-dimethylpyridazine-4-carbonitrile (1.00 g,5.97 mmol) and dipotassium carbonate (1.25 g,9.04 mmol) in acetonitrile (8.5 mL) was stirred at 70℃for 18h. The reaction was filtered, washed with EtOAc (2 times) and the filtrate was washed with brine, the organics separated, over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was then purified using a Biotage Isolena 4 flash purification system (SfarDuo 50g,0-45% etoac/heptane). The product-containing fractions were combined and evaporated in vacuo to the desired product 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carbonitrile (97.0%) as an off-white powder (1.70 g,5.66mmol, 95%).

Step 2:3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carboxamide:

3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carbonitrile (97%, 200mg,0.666 mmol) was dissolved in water (6 mL) and barium hydroxide (560 mg,3.27 mmol) was added. The resulting solution was stirred at 80℃for 17h. The solution was neutralized to pH 7 with 2M hydrochloric acid (aqueous solution) and the precipitate was filtered off. And washed with water (×3) and EtOAc (×2). The solid was dried in a vacuum oven overnight to give the desired product 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carboxamide (98.0%) as a white powder (200 mg,0.634mmol, 95%).

Step 3:3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide: to a degassed solution of 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-pyridazine-4-carboxamide (180 mg, 0.552 mmol), 1-bromo-3- (methylthio) benzene (142 mg,0.699 mmol) and cesium carbonate (567 mg,1.74 mmol) in anhydrous 1, 4-dioxane (3 mL) was added (1 e,4 e) -1, 5-diphenylpentan-1, 4-dien-3-one-palladium (3:2) (27 mg,0.0295 mmol) and (9, 9-dimethyl-9H-xanth-4, 5-diyl) bis (diphenylphosphine) (34 mg,0.0588 mmol) and the reaction was degassed for an additional 5 minutes. The vial was then sealed and the reaction stirred at 100 ℃ for 4 hours. The reaction mixture was then diluted with DCM and filtered through a phase separator. The filtrate was then washed with saturated aqueous sodium bicarbonate, brine in this order. The organic extract was then dried over anhydrous sodium sulfate under vacuum, filtered and concentrated under vacuum. The crude product was purified by column chromatography (Sfar Duo 10g, eluting with 0-100% etoac/heptane). The eluents containing the products (F41 to 54) were combined to give the desired product, 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (109 mg,0.174mmol, 30%) as a yellow solid.

Step 4: to a solution of 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (69%, 109mg,0.174 mmol) in methanol (2 mL) was added 3- (3, 4-difluoro-2-methoxyphenoxy) -5, 6-dimethyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide at room temperature: diammonium carbonate (26 mg,0.276 mmol) and bis (acetoxy) (phenyl) -lambda-3-iodoalkane (PIDA) (130 mg,0.404 mmol) and the reaction was stirred at room temperature for 17h. The reaction mixture was concentrated to dryness in vacuo to give the crude product, which was purified by preparative HPLC (acid eluting early method). The product-containing fractions were combined, evaporated in vacuo and lyophilized overnight to give the title compound, 3- (3, 4-difluoro-2-methoxy-phenoxy) -5, 6-dimethyl-N- [3- (methylsulfonyl) phenyl, as an off-white powder]Pyridazine-4-carboxamide (41 mg, 51%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.18(s,1H),8.42-8.36(m,1H),7.90-7.83(m,1H),7.74-7.67(m,1H),7.64-7.58(m,1H),7.30-7.20(m,1H),7.17-7.10(m,1H),4.24(s,1H),3.81-3.76(m,3H),3.08-3.04(m,3H),2.58(s,3H),2.33(s,3H)。m/z：463.2[M+H] ⁺ (esi+), rt=2.46 LCMS method 6.

EXAMPLE 24

Compound 1436:3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6-phenylpyridazine-4-carboxamide

Reagents and conditions: a) PdCl ₂ (dppf)、PhB(OH) ₂ 、Na ₂ CO ₃ 1, 4-dioxane, water, 90 ℃ for 1h. b) LiOH, THF, water, room temperature for 2 days. c) HATU, 3- (methylthio) aniline, DIPEA, DMF, room temperature, 2h. d) PIDA, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 16h.

Step 1:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid methyl ester: 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (1:1) (17 mg,0.0235 mmol) was added to a stirred and N2 degassed solution of 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (100 mg,0.235 mmol), phenylboronic acid (43 mg,0.353 mmol) and 2M disodium carbonate (0.35 mL,0.706 mmol) in 1, 4-dioxane (3.5 mL). The reaction mixture was stirred in a pressure flask at 90 ℃ for 1h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×20 mL) and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product. Residue (C)The residue was purified by FCC (Biotage Isolera, siO2, gradient elution 10-100% etoac in heptane) to give the title compound 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid methyl ester (85 mg,0.226mmol, 96%) as an off-white solid. LC-MS: m/z:376[ M+H ]] ⁺ (esi+), rt= 0.92METCR1704 (IPC 2 min upc gradient method).

Step 2:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid: lithium hydroxide (20 mg,0.835 mmol) was added to a stirred solution of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid methyl ester (85 mg,0.226 mmol) in THF (2 mL) and water (0.25 mL). The reaction mixture was stirred at room temperature for 2 days. 1M aqueous HCl was added to the reaction mixture to a pH of about 2 and the reaction was extracted with EtOAc (3X 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid (83.0%) as an off-white solid (64 mg,0.147mmol, 65%) which was used as such in the next step. Assuming a 100% molar yield. LC-MS: m/z 362[ M+H ] ^]+ (esi+), rt= 0.65METCR1704 (IPC 2 min upc gradient method).

Step 3:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) -6-phenyl-pyridazine-4-carboxamide: HATU (74 mg,0.195 mmol) was added to a mixture of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6-phenyl-pyridazine-4-carboxylic acid (64 mg,0.177 mmol) and N-ethyl-N-isopropyl-propan-2-amine (68 ul,0.390 mmol) in DMF (1.1 mL) at room temperature and the reaction was stirred at room temperature for 5min, followed by 3- (methylthio) aniline (33 ul, 0.268 mmol) and the reaction was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc (about 50 mL) and washed with water (3×50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. By FCC (Biotage Isolera, siO ₂ Gradient elution 10-80% EtOAc in heptane) afforded the title compound 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) -6-phenyl-pyridazine-4-carboxamide (76.0%) as a yellow gum (79 mg,0.124mmol, 70%). LC-MS: m/z 483[M+H] ⁺ (esi+), rt= 1.03METCR1704 (IPC 2 min upc gradient method).

Step 4:3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6-phenylpyridazine-4-carboxamide: to a solution of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) -6-phenyl-pyridazine-4-carboxamide (79 mg,0.164 mmol) in methanol (2.5 mL) was added 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl at room temperature ]-6-phenyl-pyridazine-4-carboxamide, phenyliodiammonium diacetate (PIDA) (121 mg,0.377 mmol) and diammonium carbonate (25 mg,0.262 mmol) and the reaction was stirred at room temperature for 16h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. The residue was purified by low pH preparative HPLC (early method). The product-containing fractions were combined and the solvent removed in vacuo to give the title compound 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl as an off-white solid]-6-phenyl-pyridazine-4-carboxamide (17 mg,0.0327mmol, 20%). ¹ H NMR(400MHz,CD ₃ OD)δ8.46(t,J＝1.9Hz,1H),8.00-7.95(m,1H),7.85-7.80(m,1H),7.66(t,J＝8.0Hz,1H),7.59-7.49(m,6H),7.48-7.39(m,2H),3.83(s,3H),3.17(s,3H),2.41(s,3H)。LC-MS：m/z 514[M+H] ⁺ (esi+), rt=2.78 min MET-uPLC-AB-107 (7 min, high pH).

Example 25

Compound 1437:3- (4-cyano-2-methoxy-phenoxy) -N- [3- (3-hydroxyazetidine-1-carbonyl) phenyl ] -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 3-hydroxyazetidine hydrochloride, HATU, DIPEA, dcm.rt,18h b) TFA, DCM, room temperature, 66h c) 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid, HATU, DIPEA, DMF, room temperature, 16h

Step 1: n- [3- (3-hydroxyazetidine-1-carbonyl) phenyl]T-butyl carbamate: to 3- [ (tert-butoxy) Carbonyl) amino group]To a mixture of benzoic acid (200 mg,0.843 mmol), HATU (385 mg,1.01 mmol) and DIPEA (442 uL,2.53 mmol) in DCM (3 mL) was added 3-hydroxyazetidine. HCl (111 mg,1.01 mmol). The reaction mixture was stirred at room temperature for 18h, then partitioned between DCM (10 mL) and water (10 mL). The layers were separated and the aqueous phase was extracted with DCM (2X 10 mL). The combined organics were washed with brine (10 mL), dried using a phase separator and concentrated under reduced pressure. The resulting crude product was purified by FCC (Biotage Isolera 4, 25g Sfar Duo, lambda-all collected) using a gradient of 0-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc to give N- [3- (3-hydroxyazetidine-1-carbonyl) phenyl as a colorless gum]Tert-butyl carbamate (68.0%) (312 mg,0.726mmol, 86%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.49(s,1H),7.75(s,1H),7.58-7.53(m,1H),7.31(t,J＝7.9Hz,1H),7.18(dt,J＝7.7,1.2Hz,1H),5.74(d,J＝6.3Hz,1H),4.52-4.45(m,1H),4.39(t,J＝7.7Hz,1H),4.27-4.18(m,1H),4.01-3.96(m,1H),3.80-3.71(m,1H),1.48(s,9H)。m/z：293.1[M+H] ⁺ (esi+), rt=0.66 LCMS method M2.

Step 2: (3-aminophenyl) - (3-hydroxyazetidin-1-yl) methanone: to N- [3- (3-hydroxyazetidine-1-carbonyl) phenyl ]]To a solution of tert-butyl carbamate (68%, 312mg,0.726 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.1 mL,14.5 mmol). The reaction mixture was stirred at room temperature for 66h, then concentrated under reduced pressure. The resulting residue was co-evaporated with DCM-heptane (1:1) three times. The crude product was dissolved in MeOH (about 1 mL) and loaded into a pre-wetted SCX-2 cartridge (5 g,25 mL). After washing with MeOH, about 2.5M NH ₃ The product was eluted with MeOH solution. The product fractions were combined and concentrated under reduced pressure to give (3-aminophenyl) - (3-hydroxyazetidin-1-yl) methanone (80.0%) as a pale yellow opaque gum (138 mg, 0.514 mmol, 79%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.05(t,J＝7.8Hz,1H),6.83-6.79(m,1H),6.69(dt,J＝7.6,1.2Hz,1H),6.65(ddd,J＝8.0,2.3,0.9Hz,1H),5.71(br.s,1H),5.23(br.s,2H),4.51-4.42(m,1H),4.41-4.32(m,1H),4.24-4.14(m,1H),4.00-3.91(m,1H),3.78-3.67(m,1H)。m/z：193.1[M+H] ⁺ (esi+), rt=0.23 LCMS method M2.

Step 3:3- (4-cyano-2-methoxy-phenoxy) -N- [3- (3-hydroxyazetidine-1-carbonyl) phenyl]-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: to a mixture of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (93%, 50mg,0.132 mmol), HATU (60 mg,0.158 mmol) and DIPEA (46 ul,0.263 mmol) in DMF (0.5 mL) was added (3-aminophenyl) - (3-hydroxyazetidin-1-yl) methanone (80%, 38mg,0.158 mmol). The reaction mixture was stirred at room temperature for 16h, then diluted with DMSO-MeCN-water (3:2:1, 1 ml), filtered and purified by preparative HPLC (preparation method 4). The product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze dried from MeCN-water (1:1). Obtaining 3- (4-cyano-2-methoxy-phenoxy) -N- [3- (3-hydroxyazetidine-1-carbonyl) phenyl in the form of a white powder]-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide (99.0%) (32 mg,0.0595mmol, 45%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.13(s,1H),8.00(t,J＝1.9Hz,1H),7.79-7.72(m,2H),7.56(dd,J＝8.2,1.8Hz,1H),7.53-7.45(m,2H),7.40(dt,J＝7.8,1.3Hz,1H),5.77(s,1H),4.57-4.39(m,2H),4.31-4.21(m,1H),4.08-3.97(m,1H),3.85-3.76(m,4H),2.52-2.51(m,3H)。m/z：528.2[M+H] ⁺ (esi+), rt=2.71 LCMS method M4.

EXAMPLE 26

Compound 1438:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (piperazine-1-carbonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Fmoc-piperazine hydrochloride, HATU, DIPEA, DCM, room temperature, 66h b) 4M HCl/dioxane, room temperature, 4h c) 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid, HATU, DIPEA, DMF, room temperature, 16h d) piperidine, meCN, room temperature, 16h

Step 1:4- [3- (tert-Butoxycarbonylamino) benzoyl]Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester: to 3- [ (tert-butoxycarbonyl) amino group]Benzoic acid (500 mg,2.11 mmol),Fmoc-piperazine hydrochloride (872 mg,2.53 mmol) was added to a mixture of HATU (962mg, 2.53 mmol) and DIPEA (1.1 mL,6.32 mmol) in DCM (7.5 mL). The reaction mixture was stirred at room temperature for 66h, then partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with DCM (2X 10 mL). The combined organics were washed with brine (20 mL), dried using a phase separator and concentrated under reduced pressure. The resulting residue was purified by FCC (Biotage Isolera 4, 25g Sfar Duo, lambda-all collected) using a 0-75% etoac/heptane gradient. The product fractions were combined and concentrated under reduced pressure to give 4- [3- (tert-butoxycarbonylamino) benzoyl as a white solid ]Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (90.0%) (1.19 g,2.03mmol, 96%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(d,J＝10.9Hz,1H),7.92-7.86(m,2H),7.86-7.82(m,1H),7.63(d,J＝7.4Hz,1H),7.56-7.45(m,2H),7.45-7.38(m,2H),7.38-7.27(m,3H),7.01-6.91(m,1H),4.40(d,J＝6.5Hz,1H),4.32-4.22(m,1H),3.63-3.45(m,3H),3.30-3.14(m,3H),2.77-2.55(m,2H),1.66-1.55(m,1H),1.51-1.45(m,9H)。LC-MS：m/z 550.3[M+Na] ⁺ (esi+), rt=1.08 LCMS method M2.

Step 2:4- (3-aminobenzoyl) piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester: 4- [3- (tert-Butoxycarbonylamino) benzoyl]Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.19 g,2.26 mmol) was dissolved in 4M HCl/dioxane (25 mL). The reaction mixture was stirred at room temperature for 4h, then concentrated under reduced pressure. The solvent was co-evaporated with DCM-heptane (1:1) to give 4- (3-aminobenzoyl) piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride (85.0%) as a pink solid (1.23 g,2.25mmol, 100%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.90(d,J＝7.4Hz,2H),7.63(d,J＝7.4Hz,2H),7.49(t,J＝8.0Hz,1H),7.42(t,J＝7.4Hz,2H),7.34(t,J＝7.8Hz,3H),7.30-7.24(m,2H),4.39(d,J＝6.5Hz,2H),4.32-4.24(m,1H),3.73-3.64(m,2H),3.55-3.43(m,4H),3.35-3.11(m,4H)。LC-MS：m/z 428.3[M+H] ⁺ (esi+), room temperature = 0.88LCMS method M2.

Step 3:4- [3- [ [3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl]Amino group]Benzoyl group]Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester: to 3- (4-cyano-2-methoxy)-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (93%, 100mg,0.263 mmol), HATU (120 mg,0.316 mmol) and DIPEA (138 ul, 0.79mmol) were added to a mixture of 9H-fluoren-9-ylmethyl 4- (3-aminobenzoyl) piperazine-1-carboxylate in DMF (1 mL; hydrochloride (85%, 172mg,0.316 mmol). The reaction mixture was stirred at room temperature for 16h, then poured into water (10 mL) and extracted with EtOAc (15 mL). The organic phase was washed with water (2X 10 mL) followed by 5% LiCl aqueous solution (2X 10 mL) over MgSO ₄ Dried and concentrated under reduced pressure. The crude product was purified by FCC (Biotage Isolera4, 10g Sfar Duo, lambda-all collected) using a 0-100% etoac/heptane gradient. The product fractions were combined and concentrated under reduced pressure to give 4- [3- [ [3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl ] as a yellow glass]Amino group]Benzoyl group]Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (88.0%) (184 mg,0.212mmol, 81%). ¹ H NMR(500MHz,CDCl ₃ )δ8.89(s,1H),7.83-7.79(m,1H),7.79-7.74(m,2H),7.68-7.66(m,1H),7.58-7.52(m,2H),7.44(t,J＝7.9Hz,1H),7.42-7.38(m,2H),7.38-7.36(m,2H),7.34-7.29(m,2H),7.27(s,1H),7.11(d,J＝7.7Hz,1H),4.54-4.50(m,2H),4.26-4.20(m,1H),3.82(s,3H),3.57-3.27(m,8H),2.60-2.55(m,3H)。LC-MS：m/z 785.1[M+Na] ⁺ (esi+), rt=1.11 LCMS method M2.

Step 4:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (piperazine-1-carbonyl) phenyl]-6- (trifluoromethyl) pyridazine-4-carboxamide: 4- [3- [ [3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl]Amino group]Benzoyl group]A solution of piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (184 mg,0.241 mmol) in acetonitrile (3 mL) was treated with piperidine (95 uL,0.965 mmol) and the mixture stirred at room temperature for 16H. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (preparation method 3). The product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to give 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (piperazine-1-carbonyl) phenyl as an off-white powder ]-6- (trifluoromethyl) pyridazine-4-carboxamide (60 mg,0.111mmol, 46%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.11(s,1H),7.76(t,J＝1.7Hz,1H),7.74(d, j=1.8 hz, 1H), 7.67 (ddd, j=8.2, 2.0,0.9hz, 1H), 7.56 (dd, j=8.2, 1.8hz, 1H), 7.51 (d, j=8.2 hz, 1H), 7.46 (t, j=7.9 hz, 1H), 7.20-7.14 (m, 1H), 3.79 (s, 3H), 3.58-3.47 (m, 2H), 3.29-3.21 (m, 2H), 2.80-2.57 (m, 4H), 2.53-2.51 (m, 3H). No piperazine NH was observed. LC-MS: m/z 541.2[ M+H ]] ⁺ (esi+), rt=2.69 LCMS method M6.

Example 27

Compound 1439:3- (4-cyano-2-methoxy-phenoxy) -N- [3- (2-methoxyethylsulfamoyl) phenyl ] -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 2-methoxyethylamine, TEA, DCM, room temperature, 17h b) iron, ammonium chloride, etOH,90 ℃,22h c) 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid, EDC-HCl, pyridine, room temperature, 4h

Step 1: n- (2-methoxyethyl) -3-nitro-benzenesulfonamide: to a mixture of 2-methoxyethylamine (94 uL,1.09 mmol) and triethylamine (0.25 mL,1.79 mmol) in DCM (4.5 mL) was added 3-nitrobenzenesulfonyl chloride (200 mg,0.902 mmol). The reaction was stirred at room temperature for 17h. The reaction mixture was then poured into NaHCO ₃ Aqueous solution and extracted with DCM (2 times). The combined organic phases were filtered through a phase separator and concentrated under reduced pressure to give the desired product N- (2-methoxyethyl) -3-nitro-benzenesulfonamide (99.0%) as a brown oil (216 mg,0.82 mmol, 91%).

Step 2: 3-amino-N- (2-methoxyethyl) benzenesulfonamide: to a solution of 3-amino-N- (2-methoxyethyl) benzenesulfonamide (92.0%) (166 mg,0.663mmol, 81%) in ethanol (6 mL) was added iron (459 mg,8.22 mmol) and ammonium chloride (440 mg,8.23 mmol) at room temperature. The resulting mixture was then stirred at 90℃for 22 hours. The reaction was filtered through celite, washed with methanol (2×20 mL) and evaporated under reduced pressure to give the crude material. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL) and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-amino-N- (2-methoxyethyl) benzenesulfonamide (92.0%) as an off-white powder (166 mg,0.663mmol, 81%).

Step 3:3- (4-cyano-2-methoxy-phenoxy) -N- [3- (2-methoxyethylsulfamoyl) phenyl]-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: to 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (93%, 50mg,0.132 mmol) and N- [3- (dimethylamino) propyl]To a solution of N' -ethylcarbodiimide hydrochloride (1:1) (51 mg,0.264 mmol) in pyridine (1 mL) was added 3-amino-N- (2-methoxyethyl) benzenesulfonamide (92%, 66mg,0.264 mmol). The mixture was stirred at room temperature for 4h. The solvent was removed (co-evaporated with MeCN) and the residue was purified by preparative HPLC (acidic early eluent method). The fractions containing the desired product were combined, evaporated and freeze-dried overnight to give the desired product, 3- (4-cyano-2-methoxy-phenoxy) -N- [3- (2-methoxyethylsulfamoyl) phenyl, as an off-white powder ]-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide (99.0%) (21 mg,0.0368mmol, 28%). ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.31 (s, 1H), 8.29-8.25 (m, 1H), 7.88-7.82 (m, 1H), 7.82-7.79 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.58 (m, 2H), 7.56 (dd, j=8.2, 1.8hz, 1H), 7.52-7.49 (m, 1H), 3.79 (s, 3H), 3.32-3.28 (m, 2H, and H) ₂ O peaks overlap), 3.15 (s, 3H), 2.96-2.91 (m, 2H), 2.53-2.51 (m, 3H, overlap DMSO peaks). m/z:566.1[ M+H ]] ⁺ (esi+), rt=3.25 LCMS method 4.

Compounds 1440 to 1445 listed in table 11 were prepared by a similar procedure as described for compound 1439 using the appropriate acid and substituted aniline.

TABLE 11

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EXAMPLE 28

Compound 1446:3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

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Reagents and conditions: a) LiOH, THF/H ₂ O, room temperature; b) 3- (methylthio) aniline, HATU, DIEA, DMF, room temperature; c) Phenyliodized ammonium diacetate, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature; d) 4-cyanophenyl) boronic acid, pd (dppf) Cl ₂ .DCM、2M Na ₂ CO ₃ Dioxane, 80 ℃.

Step 1:3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid:

to a solution of 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (200 mg,0.470 mmol) in THF (4 mL) and water (0.6 mL) was added lithium hydroxide (37 mg,1.55 mmol) at room temperature and the reaction was stirred at room temperature for 2 days. 1M aqueous HCl was added to the reaction mixture to a pH of about 2 and the reaction was extracted with EtOAc (3X 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid (91.0%) (193 mg,0.428mmol, 91%) which was used as such in the next step. Assuming a 100% molar yield. LC-MS: m/z 412[ M+H ] ] ⁺ (esi+), rt=0.55 min LCMS method 1.

Step 2:3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide: n- [ (dimethylamino) at room temperature (3H- [1,2,3]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-N-methyl-ammonium Hexafluorophosphate (HATU) (196 mg,0.516 mmol) was added to 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid (193 mg,0.469 mmol) and N-ethyl-N-isopropyl-propan-2-amine (180 uL,1.03 mmol) in DMF (3 mL)And the reaction was stirred at room temperature for 5min, followed by the addition of 3- (methylthio) aniline (87 ul,0.704 mmol) and stirring at room temperature for 16h. The reaction mixture was diluted with EtOAc (about 50 mL) and washed with water (3×about 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. By FCC (Biotage isolera, siO ₂ Gradient elution 10-50% EtOAc in heptane) afforded 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (80.0%) as a yellow gum (239 mg,0.359mmol, 77%). LC-MS: m/z 533[ M+H ]] ⁺ (esi+), rt=1.01 min LCMS method 1.

Step 3:3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: to a solution of 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (750 mg,1.41 mmol) in methanol (22 mL) was added phenyliodiammonium diacetate (PIDA) (1044 mg,3.24 mmol) and diammonium carbonate (212 mg,2.25 mmol) at room temperature and the reaction was stirred at room temperature for 16h. The reaction mixture was concentrated to dryness in vacuo to give the crude product. The residue was purified by FCC (Biotage Isolera SiO) ₂ Gradient elution of 10-100% etoac in heptane) to afford 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide (83.0%) (773 mg,1.14mmol, 81%). LC-MS: m/z 564[ M+H ]] ⁺ (esi+), rt=0.71 min LCMS method 1.

Step 4:3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide: 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (1:1) (5.8 mg, 7.99. Mu. Mol) was added to 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide (45 mg,0.0799 mmol), 4-cyanophenyl) boronic acid (23 mg,0.160 mmol) and 2M disodium carbonate (2M aqueous solution) (120 uL,0.240 mmol) in 1, 4-dioxane (1.8 mL) were stirred and N-substituted ₂ In the degassed solution. The reaction mixture was stirred in a pressure flask at 80 ℃ for 2h. The reaction mixture was diluted with EtOAc (about 3 mL) and washed with water (about 2 mL).The organic phase was dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. The residue was purified by high pH preparative HPLC (early method). The eluted products were combined and the solvent was removed by freeze drying in vacuo to give 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] as an off-white solid]Pyridazine-4-carboxamide (99.0%) (12 mg,0.0224mmol, 28%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.30(s,1H),8.39(s,1H),8.02(d,J＝8.3Hz,2H),7.87(d,J＝8.5Hz,1H),7.81(d,J＝8.3Hz,2H),7.74-7.67(m,2H),7.65-7.59(m,1H),7.58-7.53(m,1H),7.49(d,J＝8.2Hz,1H),4.24(s,1H),3.80(s,3H),3.07(s,3H),2.35(s,3H)。LC-MS：m/z 539.1[M+H] ⁺ (esi+), rt=2.60 LCMS method 7.

Compounds 1447 to 1457 listed in table 12 were prepared by similar procedures as described for step 4 of example 28 using 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide coupled with the appropriate boronic ester or acid.

Table 12

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Example 29

Compound 1458:3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (pyridin-2-yl) pyridazine-4-carboxamide

2- (tributylstannyl) pyridine (82 mg,0.224 mmol) was added to 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl at room temperature ]Pyridazine-4-carboxamide (63 mg,0.112 mmol) and CuI (2.1 mg, 0.01102 mmol) in 1, 4-dioxane (2.5 mL) and the reaction was stirred at room temperature for 5min, followed by addition of palladium-triphenylphosphine (1:4) (13 mg, 0.01102 mmol) and stirring at 110℃for 16h. The reaction mixture was diluted with EtOAc (about 3 mL) and washed with 1M KF aqueous solution, the mixture was stirred at room temperature for 15min and filtered through a celite pad. The layers were separated and the organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product. The residue was purified by low pH preparative HPLC (early method). The products containing the fractions were combined and the solvent was removed by freeze drying in vacuo. The crude product was taken up in CH ₃ CN (3 mL) and MP-TMT (200 mg,0.132mmol,0.66 mmol/g) were diluted and stirred at room temperature for about 16h. The product was diluted in 1:1acn: h ₂ O (about 3 ml) and concentrated to dryness by freeze drying overnight to give 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl) as an off-white solid]-6- (2-pyridinyl) pyridazine-4-carboxamide (98.0%) (21 mg,0.0404mmol, 36%). ¹ H NMR(500MHz,CD ₃ OD)δ8.79-8.65(m,1H),8.47(t,J＝1.9Hz,1H),8.06-8.01(m,1H),8.01-7.95(m,1H),7.88-7.80(m,2H),7.66(t,J＝8.0Hz,1H),7.58-7.50(m,2H),7.49-7.38(m,2H),3.83(s,3H),3.18(s,3H),2.51(s,3H)。

Compounds 1459 through 1464 listed in table 13 were prepared by an analogous procedure as described for example 29 using the appropriate substituted R-SnBu3 and 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonylmethyl) phenyl ] pyridazine-4-carboxamide.

TABLE 13

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Example 30

Compound 1465:3- (4-cyano-2-methylphenoxy) -N- (3-methanesulfonylphenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.42(br.s,1H),8.39-8.33(m,1H),7.93-7.85(m,2H),7.81(dd,J＝8.4,1.8Hz,1H),7.77-7.66(m,2H),7.50(d,J＝8.4Hz,1H),3.24(s,3H),2.56-2.53(m,3H),2.17(s,3H)。m/z：491.0[M+H] ⁺ (esi+), rt=3.28 LCMS method 4.

Example 31

Compound 1466:3- (4-fluoro-2-methylphenoxy) -5-methyl-N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.30(s,1H),8.34-8.29(m,1H),7.77(dt,J＝7.5,1.8Hz,1H),7.67-7.58(m,2H),7.44(s,2H),7.29(dd,J＝8.9,5.1Hz,1H),7.24(dd,J＝9.4,3.0Hz,1H),7.14(td,J＝8.6,3.2Hz,1H),2.53-2.51(m,3H),2.12(s,3H)。m/z：485.0[M+H] ⁺ (esi+), rt=3.97 LCMS method 5.

Example 32

Compound 1467:3- [ 2-fluoro-4- (trifluoromethoxy) phenoxy ] -N- (3-methanesulfonylphenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD) δ8.41 (t, j=1.9 hz, 1H), 7.98 (ddd, j=8.1, 2.1,1.0hz, 1H), 7.79 (ddd, j=7.8, 1.6,1.0hz, 1H), 7.68 (t, j=8.0 hz, 1H), 7.54 (t, j=8.8 hz, 1H), 7.37 (dd, j=10.5, 2.4hz, 1H), 7.28-7.22 (m, 1H), 3.15 (s, 3H), 2.62-2.58 (m, 3H). No 1 proton (NH) was observed. m/z:554.0[ M+H ]] ⁺ (esi+), rt=3.78 LCMS method 4.

Example 33

Compound 1468: n- (3-methanesulfonylphenyl) -5-methyl-3- { [ 2-methyl-6- (trifluoromethyl) pyridin-3-yl ] oxy } -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ8.41(t,J＝1.9Hz,1H),7.97(ddd,J＝8.2,2.2,1.0Hz,1H),7.94(d,J＝8.5Hz,1H),7.81-7.76(m,2H),7.69(t,J＝8.0Hz,1H),3.15(s,3H),2.62(q,J＝1.5Hz,3H),2.47(s,3H)。m/z：535.5[M+H] ⁺ (esi+), rt=3.62 LCMS method 4.

Example 34

Compound 1469:3- [ (6-bromo-2-methylpyridin-3-yl) oxy ] -N- (3-methanesulfonylphenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ8.40(t,J＝2.0Hz,1H),7.96(ddd,J＝8.1,2.2,1.1Hz,1H),7.79(ddd,J＝7.8,1.7,1.0Hz,1H),7.71-7.62(m,2H),7.56-7.51(m,1H),3.15(s,3H),2.60(q,J＝1.5Hz,3H),2.37(s,3H)。m/z：545.3,547.3[M+H] ⁺ (esi+), rt=3.44 LCMS method 4.

Example 35

Compound 1470:3- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methoxy ] -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ8.41(t,J＝2.0Hz,1H),7.93(ddd,J＝8.1,2.2,1.0Hz,1H),7.85(ddd,J＝7.9,1.9,1.0Hz,1H),7.67(t,J＝8.0Hz,1H),4.88(s,2H),3.18(s,3H),2.52-2.49(m,3H),2.02(d,J＝2.5Hz,7H)。m/z：473.4[M+H] ⁺ (esi+), rt=2.94 LCMS method 4

Example 36

A compound: 1471 and 1472

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The following chiral separation conditions were used to isolate 3- (4-chloro-2-fluoro-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl]Racemic mixtures of 6- (trifluoromethyl) pyridazine-4-carboxamide. Mobile phase: 85% heptane, 15% ethanol. Column: chiralpak AS, 20X 250mm,10 μm. Flow rate: 18mL/min. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.35(s,1H),8.35(t,J＝1.8Hz,1H),7.91-7.86(m,1H),7.76-7.71(m,2H),7.64(t,J＝7.9Hz,1H),7.54(t,J＝8.6Hz,1H),7.45-7.41(m,1H),4.26(s,1H),3.11-3.04(m,3H),2.54-2.52(m,3H)。m/z：503.1,505.1[M+H] ⁺ (esi+), rt=3.13 MET-uPLC-AB-101 (7 min, low pH) and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.36(s,1H),8.35(t,J＝1.8Hz,1H),7.91-7.86(m,1H),7.76-7.70(m,2H),7.64(t,J＝7.9Hz,1H),7.54(t,J＝8.6Hz,1H),7.45-7.41(m,1H),4.27(s,1H),3.13-3.03(m,3H),2.54-2.52(m,3H)。m/z：503.1,505.1[M+H] ⁺ (esi+), rt=3.13 MET-uPLC-AB-101 (7 min, low pH).

EXAMPLE 37

A compound: 1473 and 1474

3- (3, 4-difluoro-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl was isolated using the following chiral separation conditions]Racemic mixture of 6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase 85:15 heptane ethanol. Column Chiralpak AS, 20X 250mm,10 μm. Flow rate (mL/min) 18. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(t,J＝1.8Hz,1H),7.87(d,J＝8.1Hz,1H),7.73(d,J＝7.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.33-7.26(m,1H),7.24(ddd,J＝9.3,5.3,1.8Hz,1H),4.26(s,1H),3.87-3.76(m,3H),3.11-2.99(m,3H),2.54-2.52(m,3H)。m/z：516.9[M+H] ⁺ (esi+), rt= 3.85METCR1416 Hi res 7min and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.32(s,1H),8.36(t,J＝1.9Hz,1H),7.90-7.84(m,1H),7.73(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.34-7.26(m,1H),7.24(ddd,J＝9.3,5.3,1.9Hz,1H),4.26(s,1H),3.85-3.76(m,3H),3.10-3.02(m,3H),2.54-2.52(m,3H)。m/z：516.9[M+H] ⁺ ,(ESI+),RT＝3.86METCR1416 Hi res 7min。

Example 38

A compound: 1475 and 1476

Compound 1475:3- (3, 4-difluoro-2-methoxy-phenoxy) -5-methyl-N- (3-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.24(br.s,1H),8.82(d,J＝2.3Hz,1H),8.39(dd,J＝4.7,1.4Hz,1H),8.16(ddd,J＝8.3,2.6,1.5Hz,1H),7.45(dd,J＝8.1,4.5Hz,1H),7.34-7.20(m,2H),3.84-3.78(m,3H),2.54-2.52(m,3H)。m/z：441.1[M+H] ⁺ (esi+), rt=3.00 MET-uPLC-AB-101 (7 min, low pH).

Compound 1476:3- (3, 4-difluoro-2-methoxy-phenoxy) -5-methyl-N- (1-oxopyridin-1-ium-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.48(br.s,1H),8.72(t,J＝1.6Hz,1H),8.11-8.05(m,1H),7.54-7.48(m,1H),7.44(dd,J＝8.4,6.3Hz,1H),7.36-7.20(m,2H),3.85-3.78(m,3H),2.54-2.52(m,3H)。m/z：457.1[M+H] ⁺ (esi+), rt=2.77 MET-uPLC-AB-101 (7 min, low pH).

Example 39

A compound: 1477 and 1478

3- [2, 3-difluoro-4- (trifluoromethoxy) phenoxy was isolated using the following chiral separation conditions]-5-methyl-N- [3- (methylsulfonyl) phenyl ]]Racemic mixture of 6- (trifluoromethyl) pyridazine-4-carboxamide: 10% IPA,90% CO ₂ Chiralpak IC, 10X 250mm,5 μm,15mL/min, sample in methanol, IPA. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.38(s,1H),8.34(t,J＝1.8Hz,1H),7.92-7.84(m,1H),7.74(d,J＝7.8Hz,1H),7.70-7.59(m,2H),7.58-7.49(m,1H),4.26(s,1H),3.12-3.03(m,3H),2.56-2.53(m,3H)。LC-MS：m/z 571.6[M+H] ⁺ (esi+), rt=4.24 LCMS method 5 and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.41(s,1H),8.35(s,1H),7.88(d,J＝7.8Hz,1H),7.79-7.70(m,1H),7.64(t,J＝8.0Hz,2H),7.57-7.50(m,1H),4.27(s,1H),3.08(s,3H),2.57-2.53(m,3H)。LC-MS：m/z 571.1[M+H] ⁺ (esi+), rt=3.48 LCMS procedure M2.

Example 40

A compound: 1479 and 1480

The following chiral separation conditions were used to isolate 3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazineRacemic mixture of 4-formamide: mobile phase 20% methanol 80% CO ₂ The method comprises the steps of carrying out a first treatment on the surface of the Column Chiralpak IC,10×250mm,5 μm; flow rate (mL/min) 15. First eluting isomer (S) -3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide ¹ H NMR(400MHz,DMSO-d ₆ )δ11.29(s,1H),8.33(t,J＝2.0Hz,1H),7.88-7.83(m,1H),7.75-7.68(m,2H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.3,1.8Hz,1H),7.49(d,J＝8.2Hz,1H),4.24(s,1H),3.77(s,3H),3.05(d,J＝1.1Hz,3H),2.51-2.50(m,3H)。m/z：506.3[M+H] ⁺ (esi+), rt=2.89 LCMS method 6 and second eluting isomer (R) -3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide ¹ H NMR(400MHz,DMSO-d ₆ )δ11.29(s,1H),8.33(t,J＝2.0Hz,1H),7.89-7.82(m,1H),7.75-7.68(m,2H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.8Hz,1H),7.49(d,J＝8.2Hz,1H),4.24(s,1H),3.77(s,3H),3.05(d,J＝1.1Hz,3H),2.51-2.50(m,3H)。m/z：506.3[M+H] ⁺ (esi+), rt=2.89 LCMS method 6.

Example 41

A compound: 1481 and 1482

The racemic mixture of 3- (4-chloro-2-methoxyphenoxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide was separated using the following chiral separation conditions: chiral separation: 85% heptane, 15% ethanol, chiralpak AS, 20X 250mm,10 μm,18mL/min, samples in methanol, ethanol. First eluting isomer 1H NMR (500 MHz, DMSO-d ₆ ) δ11.29 (s, 1H), 8.36 (t, j=1.8 hz, 1H), 7.89-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.63 (t, j=7.9 hz, 1H), 7.33-7.29 (m, 2H), 7.10 (dd, j=8.6, 2.3hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H), 3.09-3.05 (m, 3H). 3H (one Me) was not observed-hidden by DMSO signal. m/z:503.1,505.1[ M+H ]] ⁺ (esi+), rt=3.06 LCMS method 4 and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.29(s,1H)8.36 (t, j=1.8 hz, 1H), 7.90-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.63 (t, j=7.9 hz, 1H), 7.33-7.28 (m, 2H), 7.10 (dd, j=8.6, 2.3hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H), 3.10-3.04 (m, 3H). 3H (one CH) ₃ ) No-hiding by DMSO signal was observed. m/z:503.1,505.1[ M+H ]] ⁺ (esi+), rt=3.13 LCMS method 4.

Example 42

Compound 1483:3- [ (2, 6-dimethylpyridin-3-yl) oxy)]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.34(s,1H),8.37(t,J＝1.9Hz,1H),8.13(s,1H),7.89-7.84(m,1H),7.77-7.71(m,1H),7.65(t,J＝7.9Hz,1H),7.61(d,J＝8.2Hz,1H),7.23(d,J＝8.2Hz,1H),3.17(s,1H),3.12(s,3H),2.54-2.52(m,3H),2.47(s,3H),2.28(s,3H)。m/z：480.3[M+H] ⁺ (esi+), rt=2.74 LCMS method 6.

EXAMPLE 43

A compound: 1484 and 1485

3- [ (2, 6-lutidine-3-yl) oxy was isolated using the following chiral separation conditions]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Racemic mixture of phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase 70:30 heptane: ipa+0.2% dea. Column Cellulose-4,21.2 ×250mm,5 μm; flow rate (mL/min) 9. First eluting isomer ¹ H NMR(500MHz,CD ₃ OD)δ8.33(t,J＝2.0Hz,1H),7.84(ddd,J＝8.2,2.2,1.0Hz,1H),7.72(ddd,J＝7.8,1.8,1.0Hz,1H),7.54(t,J＝8.0Hz,1H),7.48(d,J＝8.3Hz,1H),7.12(d,J＝8.4Hz,1H),3.05(s,3H),2.47(q,J＝1.5Hz,3H),2.41(s,3H),2.24(s,3H)。m/z：480.3[M+H] ⁺ (esi+), rt=2.55 LCMS method 6 and second eluting isomer ¹ H NMR(500MHz,CD ₃ OD)δ8.33(t,J＝2.0Hz,1H),7.84(ddd,J＝8.1,2.2,1.0Hz,1H),7.72(ddd,J＝7.9,1.9,1.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.48(d,J＝8.4Hz,1H),7.12(d,J＝8.3Hz,1H),3.05(s,3H),2.48(q,J＝1.5Hz,3H),2.41(s,3H),2.24(s,3H)。m/z：480.3[M+H] ⁺ (esi+), rt=2.54 LCMS method 6.

EXAMPLE 44

Compound 1486:3- (4-chloro-3-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO)δ11.35(s,1H),8.36(s,1H),7.87(d,J＝8.7Hz,1H),7.74(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.57(t,J＝8.6Hz,1H),7.23(d,J＝8.9Hz,1H),4.27(s,1H),3.08(s,3H),2.56-2.51(m,3H),2.11(d,J＝1.9Hz,3H)。m/z：517.1,519.1[M+H] ⁺ (esi+), rt=3.30 LCMS method 4

Example 45

A compound: 1487 and 1488

3- (4-chloro-3-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl was isolated using the following chiral separation conditions]Racemic mixture of 6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase 15% methanol, 85% co ₂ The method comprises the steps of carrying out a first treatment on the surface of the Column Chiralpak AS-H, 10X 250mm,5 μm; flow rate (mL/min) 15. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.34(s,1H),8.35(t,J＝2.0Hz,1H),7.90-7.81(m,1H),7.73(d,J＝7.7Hz,1H),7.64(t,J＝7.9Hz,1H),7.56(t,J＝8.6Hz,1H),7.22(dd,J＝8.9,1.6Hz,1H),4.26(s,1H),3.07(d,J＝1.1Hz,3H),2.54-2.51(m,3H),2.10(d,J＝2.2Hz,3H)。m/z：517.4,519.4[M+H] ⁺ (esi+), rt=3.42 LCMS method 4 and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.34(s,1H),8.35(t,J＝2.0Hz,1H),7.89-7.80(m,1H),7.73(d,J＝7.8Hz,1H),7.63(t,J＝7.9Hz,1H),7.56(t,J＝8.6Hz,1H),7.22(dd,J＝8.9,1.6Hz,1H),4.26(s,1H),3.07(d,J＝1.1Hz,3H),2.54-2.52(m,3H),2.12-2.08(m,3H)。m/z：517.4,519.4[M+H] ⁺ (esi+), rt=3.42 LCMS method 4.

Example 46

Compound 1489:3- (4-chloro-3-fluoro-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.34(s,1H),8.36(t,J＝1.9Hz,1H),7.93-7.84(m,1H),7.74(d,J＝8.1Hz,1H),7.65(t,J＝7.9Hz,1H),7.45(dd,J＝9.0,7.8Hz,1H),7.28(dd,J＝9.0,2.0Hz,1H),4.27(s,1H),3.80(d,J＝1.3Hz,3H),3.08(d,J＝0.8Hz,3H),2.56-2.51(m,3H)。m/z：533.1,535.1[M+H] ⁺ (esi+), rt=3.21 LCMS method 4.

Example 47

A compound: 1490 and 1491

3- (4-chloro-3-fluoro-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl was isolated using the following chiral separation conditions]Racemic mixture of 6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase 15% methanol, 85% co ₂ The method comprises the steps of carrying out a first treatment on the surface of the Column Chiralpak AS-H, 10X 250mm,5 μm; flow rate (mL/min) 15. First eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.33(s,1H),8.35(s,1H),7.87(d,J＝8.0Hz,1H),7.73(d,J＝7.8Hz,1H),7.63(t,J＝7.9Hz,1H),7.44(dd,J＝9.0,7.7Hz,1H),7.27(dd,J＝9.0,1.9Hz,1H),4.26(s,1H),3.79(d,J＝1.3Hz,3H),3.07(d,J＝1.1Hz,3H),2.54-2.52(m,3H)。m/z：533.1,535.1[M+H] ⁺ (esi+), rt=3.22 LCMS method 4 and second eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.34(s,1H),8.35(t,J＝1.9Hz,1H),7.92-7.83(m,1H),7.73(d,J＝7.8Hz,1H),7.64(t,J＝7.9Hz,1H),7.44(dd,J＝9.0,7.7Hz,1H),7.27(dd,J＝9.0,2.0Hz,1H),4.27(s,1H),3.79(d,J＝1.3Hz,3H),3.07(d,J＝1.1Hz,3H),2.55-2.52(m,3H)。m/z：533.1,535.1[M+H] ⁺ (esi+), rt=3.22 LCMS method 4.

EXAMPLE 48

Compound 1492:3- [4- (Cyclobutoxy) -2, 3-difluoro-phenoxy ] -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ8.47(t,J＝1.9Hz,1H),7.98(m,1H),7.86(m,1H),7.68(t,J＝8.0Hz,1H),7.11(td,J＝8.7,2.4Hz,1H),6.90-6.81(m,1H),4.80(p,J＝6.9Hz,1H),3.19(s,3H),2.61(d,J＝1.4Hz,3H),2.57-2.45(m,2H),2.29-2.15(m,2H),1.90(m,1H),1.84-1.67(m,1H)。m/z：557.3[M+H] ⁺ (esi+), rt=3.63 LCMS method 6.

Example 49

A compound: 1493 and 1494

Isolation of 3- (4-cyclobutoxy-2, 3-difluorophenoxy) -N- {3- [ imino (meth) oxy ] - λ using the following chiral separation conditions ⁶ Thio group]Racemic mixture of phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase 15% methanol, 85% co ₂ The method comprises the steps of carrying out a first treatment on the surface of the Column Chiralpak AS-H, 10X 250mm,5 μm; flow rate (mL/min) 15. First eluting isomer ¹ H NMR(400MHz,CD ₃ OD)δ8.47(t,J＝1.9Hz,2H),8.02-7.94(m,1H),7.86(d,J＝8.6Hz,1H),7.68(t,J＝8.0Hz,1H),7.16-7.07(m,1H),6.90-6.81(m,1H),4.86-4.74(m,1H),3.19(s,3H),2.61(d,J＝1.4Hz,3H),2.57-2.45(m,2H),2.29-2.15(m,2H),1.91(m,1H),1.84-1.68(m,1H)。m/z：557.2[M+H] ⁺ (esi+), rt=2.16 and secondEluting the isomer ¹ H NMR(400MHz,CD ₃ OD)δ8.47(t,J＝1.9Hz,1H),7.98(m,1H),7.86(d,J＝7.9Hz,1H),7.68(t,J＝8.0Hz,1H),7.16-7.07(m,1H),6.90-6.81(m,1H),4.80(p,J＝7.1Hz,1H),3.19(s,3H),2.63-2.58(m,3H),2.51(m,2H),2.29-2.15(m,2H),1.90(m,1H),1.76(m,1H)。m/z：557.2[M+H] ⁺ (esi+), rt=3.81 chiral LC.

Example 50

Compound 1495:3- [ 2-fluoro-4- (trifluoromethoxy) phenoxy ] -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.37(s,1H),8.35(t,J＝1.9Hz,1H),7.89(ddd,J＝8.0,2.0,0.9Hz,1H),7.77-7.69(m,2H),7.69-7.61(m,2H),7.44-7.37(m,1H),4.26(s,1H),3.10-3.06(m,3H),2.55-2.52(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.36 LCMS method 4.

Example 51

A compound: 1496 and 1497

3- [ 2-fluoro-4- (trifluoromethoxy) phenoxy was isolated using the following chiral separation conditions]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Racemic mixture of phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: chiral separation: 10% methanol, 90% CO ₂ Chiralpak IC, 10X 250mm,5 μm,15mL/min, samples in methanol. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.37(s,1H),8.38-8.32(m,1H),7.92-7.85(m,1H),7.76-7.70(m,2H),7.68-7.61(m,2H),7.40(d,J＝9.0Hz,1H),4.26(s,1H),3.07(s,3H),2.55-2.52(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.36 LCMS method 4 and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.37(s,1H),8.37-8.33(m,1H),7.91-7.86(m,1H),7.77-7.69(m,2H),7.69-7.61(m,2H),7.40(d,J＝9.1Hz,1H),4.26(s,1H),3.08(s,3H),2.55-2.52(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.36 LCMS method 4.

Example 52

Compound 1498:3- [ (6-Cyclobutoxy-2-methylpyridin-3-yl) oxy]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.40(s,1H),8.37(s,1H),7.88(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),7.69-7.60(m,2H),6.72(d,J＝8.7Hz,1H),5.10(p,J＝7.2Hz,1H),4.27(s,1H),3.08(s,3H),2.45-2.36(m,2H),2.22(s,3H),2.05(m,2H),1.78(m,1H),1.64(m,1H)。m/z：536.2[M+H] ⁺ (esi+), rt=3.35 LCMS method 4.

Example 53

A compound: 1499 and 1500

The following chiral separation conditions were used to isolate a racemic mixture of 3- ((6-cyclobutoxy-2-methylpyridin-3-yl) oxy) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: 100% ethanol, chirapak AD-H, 20X 250mm,5 μm,9mL/min. First eluting isomer ¹ H NMR(500MHz,CD ₃ OD)δδ8.47(t,J＝1.9Hz,1H),7.98(m,1H),7.89-7.83(m,1H),7.68(t,J＝8.0Hz,1H),7.55(d,J＝8.8Hz,1H),6.66(d,J＝8.8Hz,1H),5.13(p,J＝7.3Hz,1H),3.19(s,3H),2.61(d,J＝1.3Hz,3H),2.53-2.42(m,2H),2.28(s,3H),2.14(m,2H),1.93-1.80(m,1H),1.72(m,1H)。m/z：536.2[M+H] ⁺ (esi+), rt=3.35 MET-uPLC-AB-101 (7 min, low pH LCMS method 4 and second eluting isomer ¹ H NMR(500MHz,CD ³ OD)δ8.47(t,J＝1.9Hz,1H),7.98(m,1H),7.86(m,1H),7.69(t,J＝8.0Hz,1H),7.55(d,J＝8.8Hz,1H),6.67(d,J＝8.8Hz,1H),5.14(p,J＝7.2Hz,1H),3.19(s,1H),2.61(d,J＝1.3Hz,3H),2.54-2.43(m,2H),2.28(s,3H),2.14(m,2H),1.93-1.81(m,1H),1.72(m,1H)。

Example 54

Compound 1501:3- [2, 3-difluoro-4- (prop-2-yloxy) phenoxy]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.37(s,1H),8.35(t,J＝1.8Hz,1H),7.92-7.85(m,1H),7.78-7.70(m,1H),7.64(t,J＝7.9Hz,1H),7.29-7.20(m,1H),7.18-7.11(m,1H),4.71(hept,J＝6.0Hz,1H),4.27(s,1H),3.08(s,3H),2.54-2.51(m,3H),1.32(d,J＝6.0Hz,6H)。m/z：545.3[M+H] ⁺ (esi+), rt=3.53 LCMS method 6.

Example 55

A compound: 1502 and 1503

The racemic mixture of 3- (2, 3-difluoro-4-isopropoxyphenoxy) -5-methyl-N- (3- (S-methanesulfonimidoyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide was separated using the following chiral separation conditions: 80% heptane, 20%IPA,Chiralpak AS,20X 250mm,10 μm,18mL/min, sample in methanol, IPA. First eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.36(br.s,1H),8.37-8.33(m,1H),7.91-7.85(m,1H),7.77-7.71(m,1H),7.64(t,J＝7.9Hz,1H),7.29-7.20(m,1H),7.18-7.10(m,1H),4.71(hept,J＝5.9Hz,1H),4.27(s,1H),3.10-3.05(m,3H),2.55-2.51(m,3H),1.32(d,J＝6.0Hz,6H)。LC-MS：m/z 545.3[M+H] ⁺ (esi+), rt=3.50 LCMS method 6 and second eluting isomer ¹ HNMR(400MHz,DMSO-d ₆ )δ11.36(br.s,1H),8.37-8.33(m,1H),7.91-7.85(m,1H),7.77-7.71(m,1H),7.64(t,J＝7.9Hz,1H),7.29-7.20(m,1H),7.19-7.10(m,1H),4.71(hept,J＝5.9Hz,1H),4.27(s,1H),3.08(s,3H),2.54-2.52(m,3H),1.32(d,J＝6.0Hz,6H)。LC-MS：m/z 545.3[M+H] ⁺ (esi+), rt=3.51 LCMS method 6.

Example 56

Compound 1504:3- (3-fluoro-4-methoxy-2-methylphenoxy) -N- {3- [ imino (methyl) oxy ] - λ ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ8.45(t,J＝2.0Hz,1H),7.96(ddd,J＝8.1,2.1,1.0Hz,1H),7.84(ddd,J＝7.9,1.9,1.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.04-6.95(m,2H),3.88(s,3H),3.17(s,3H),2.58(q,J＝1.5Hz,3H),2.07(d,J＝2.2Hz,3H)。m/z：513.3[M+H] ⁺ (esi+), rt=3.12 LCMS method 6.

Example 57

A compound: 1505 and 1506

Isolation of 3- (3-fluoro-4-methoxy-2-methylphenoxy) -N- {3- [ imino (meth) oxy ] -lambda using the following chiral separation conditions ⁶ Thio group]Racemic mixture of phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase: 10% methanol: 90% CO ₂ Column: chiralpak AS-H, 10X 250mm,5 μm; flow rate (mL/min) 15. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.31(s,1H),8.34(t,J＝1.8Hz,1H),7.90-7.80(m,1H),7.72(d,J＝7.8Hz,1H),7.62(t,J＝7.9Hz,1H),7.13-7.01(m,2H),4.25(s,1H),3.83(s,3H),3.06(d,J＝1.1Hz,3H),2.51-2.50(m,3H),2.01(d,J＝2.2Hz,3H)。m/z：513.3[M+H] ⁺ (esi+), rt=3.13 LCMS method 6 and second eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.31(s,1H),8.34(t,J＝2.0Hz,1H),7.88-7.81(m,1H),7.72(d,J＝7.8Hz,1H),7.62(t,J＝7.9Hz,1H),7.13-7.02(m,2H),4.25(s,1H),3.83(s,3H),3.06(d,J＝1.1Hz,3H),2.51-2.50(m,3H),2.01(d,J＝2.1Hz,3H)。m/z：513.3[M+H] ⁺ (esi+), rt=3.13 LCMS method 6.

Example 58

Compound 1507: n- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -3- [ (6-methoxy-2-methylpyridin-3-yl) oxy]-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.45(t,J＝2.0Hz,1H),7.96(ddd,J＝8.2,2.2,1.0Hz,1H),7.84(ddd,J＝7.8,1.8,1.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.54(d,J＝8.8Hz,1H),6.70(d,J＝8.7Hz,1H),3.91(s,3H),3.17(s,3H),2.59(q,J＝1.6Hz,3H),2.28(s,3H)。m/z：496.3[M+H] ⁺ (esi+), rt=2.96 LCMS method 6.

Example 59

A compound: 1508 and 1509

Isolation of N- {3- [ imino (meth) oxo-lambda ] using the following chiral separation conditions ⁶ Thio group ]Phenyl } -3- [ (6-methoxy-2-methylpyridin-3-yl) oxy]Racemic mixture of 5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase: 85:15 heptane to ethanol; column: chiralpak AS, 20X 250mm,10 μm; flow rate (mL/min) 18. First eluting isomer ¹ H NMR(500MHz,DMSO-d ₆ )δ11.30(s,1H),8.34(t,J＝2.0Hz,1H),7.89-7.83(m,1H),7.72(d,J＝7.8Hz,1H),7.65-7.59(m,2H),6.75(d,J＝8.5Hz,1H),4.25(s,1H),3.84(s,3H),3.06(d,J＝1.1Hz,3H),2.51-2.50(m,3H),2.23(s,3H)。m/z：496.3[M+H] ⁺ (esi+), rt=2.95 LCMS method 6 and second eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.31(s,1H),8.34(t,J＝2.0Hz,1H),7.87-7.81(m,1H),7.75-7.68(m,1H),7.66-7.57(m,2H),6.75(d,J＝8.8Hz,1H),4.25(s,1H),3.84(s,3H),3.06(d,J＝1.2Hz,3H),2.51-2.50(m,3H),2.23(s,3H)。m/z：496.3[M+H] ⁺ (esi+), rt=2.95 LCMS method 6.

Example 60

Compound 1510:3- [4- (difluoromethoxy) -2, 3-difluoro-phenoxy ] -5-methyl-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.39(s,1H),8.36(t,J＝1.8Hz,1H),7.89(dd,J＝8.1,1.1Hz,1H),7.78-7.72(m,1H),7.65(t,J＝7.9Hz,1H),7.53-7.17(m,3H),4.28(s,1H),3.09(s,3H),2.57-2.53(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.18 LCMS method 4.

Example 61

A compound: 1511 and 1512

3- [4- (difluoromethoxy) -2, 3-difluorophenoxy was isolated using the following chiral separation conditions]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Racemic mixture of phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: mobile phase: 85:15 heptane to ethanol; column: chiralpak AD-H, 20X 250mm,5 μm; flow Rate (mL/min): 18mL/min, samples in ethanol, methanol and acetonitrile. First eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.37(s,1H),8.34(t,J＝2.0Hz,1H),7.88(ddd,J＝8.0,2.2,1.1Hz,1H),7.78-7.70(m,1H),7.64(t,J＝7.9Hz,1H),7.55-7.14(m,3H),4.27(d,J＝1.4Hz,1H),3.08(d,J＝1.1Hz,3H),2.56-2.53(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.19 LCMS method 4 and second eluting isomer ¹ H NMR(400MHz,DMSO-d ₆ )δ11.39(s,1H),8.34(t,J＝2.0Hz,1H),7.88(ddd,J＝7.9,2.2,1.1Hz,1H),7.76-7.70(m,1H),7.64(t,J＝7.9Hz,1H),7.54-7.14(m,3H),4.27(s,1H),3.08(d,J＝1.2Hz,3H),2.56-2.53(m,3H)。m/z：553.1[M+H] ⁺ (esi+), rt=3.19 LCMS method 4.

Example 62

Compound 1513:3- (4-carbamoyl-phenoxy) -N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.32(s,1H),8.33(t,J＝2.0Hz,1H),8.01(s,1H),7.99-7.94(m,2H),7.87(ddd,J＝8.1,2.1,1.1Hz,1H),7.71(ddd,J＝7.8,1.8,1.1Hz,1H),7.62(t,J＝8.0Hz,1H),7.40(s,1H),7.38-7.34(m,2H),4.29-4.18(m,1H),3.11-3.01(m,3H),2.51-2.50(m,3H)。m/z：494.5[M+H] ⁺ (esi+), rt=2.19 LCMS method 4.

Example 63

Compound 1514:3- [2, 6-difluoro-4- (trifluoromethoxy) phenoxy]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR (400 mhz, cd3 od) δ8.46 (t, j=1.9 hz, 1H), 7.96 (ddd, j=8.1, 2.1,0.9hz, 1H), 7.85 (ddd, j=7.9, 1.7,1.0hz, 1H), 7.67 (t, j=8.0 hz, 1H), 7.29 (d, j=8.6 hz, 2H), 3.18 (s, 3H), 2.61 (d, j=1.4 hz, 3H) were not found 2NH. m/z:571[ M+H ]] ⁺ (esi+), rt=3.55 LCMS method 4.

Example 64

Compound 1515:3- [ 3-fluoro-2-methyl-4- (trifluoromethoxy) phenoxy]-N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.38(br.s,1H),8.35(t,J＝1.8Hz,1H),7.90-7.84(m,1H),7.77-7.70(m,1H),7.64(t,J＝7.9Hz,1H),7.56(t,J＝8.8Hz,1H),7.30(dd,J＝9.1,1.6Hz,1H),4.26(s,1H),3.07(s,3H),2.55 -2.52(m,3H),2.14-2.10(m,3H)。m/z：567.3[M+H] ⁺ (esi+), rt=3.66 LCMS method 6.

Example 65

Compound 1516:3- (3, 4-difluoro-2-methoxyphenoxy) -N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5H,6H, 7H-cyclopenta [ c ]]Pyridazine-4-carboxamides

¹ H NMR(400MHz,DMSO-d ₆ )δ11.12(s,1H),8.38(t,J＝1.8Hz,1H),7.88(ddd,J＝8.0,2.0,1.0Hz,1H),7.70(dt,J＝7.8,1.1Hz,1H),7.61(t,J＝7.9Hz,1H),7.30-7.21(m,1H),7.17(ddd,J＝9.3,5.3,2.0Hz,1H),4.24(s,1H),3.82-3.75(m,3H),3.12-3.02(m,7H),2.22-2.12(m,2H)。m/z：475.3[M+H] ⁺ (esi+), rt=2.54 LCMS method 6.

Example 66

Compound 1517: (S) -3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 4-fluoro-2-methoxyphenol, K ₂ CO ₃ Acetonitrile, 70 ℃; b) NaI, CH ₃ COCl, acetonitrile, 0 ℃; c) Difluoro (fluoro sulfonyl) methyl acetate, cuI, TBAI, DMF,70 ℃; d) 2, 6-tetramethylpiperidine, n-BuLi (2.5M/hexane), 1-iodopyrrolidine-2, 5-dione, THF, -78deg.C; e) 5.4M NaOMe/MeOH, 0deg.C to room temperature; f) LiOH, THF, H ₂ O (8:2, v/v), room temperature; g) (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -sub-Sulfanyl) tert-butyl carbamate; h) 4M HCl/dioxane, 1, 4-dioxane.

Step 1: 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylic acid methyl ester

4-fluoro-2-methoxyphenol (98%, 3.86g,26.6 mmol), methyl 3, 6-dichloropyridazine-4-carboxylate (5.25 g,25.4 mmol), and K ₂ CO ₃ A mixture of (5.26 g,38.0 mmol) in acetonitrile (52 mL) was stirred at 70℃for 3.5h. The reaction mixture was cooled to room temperature, filtered through a phase separator, washed with DCM (3×50 mL) and concentrated in vacuo. The compound was purified by FCC using 0-100% etoac/heptane over silica (on a Biotage Sfar 100g column, using DCM to wet the supported compound) and concentrated in vacuo to give methyl 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylate (71.0%) as a pale yellow solid (6.26 g, 56%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.26(s,1H),7.29(dd,J＝8.8,5.8Hz,1H),7.14(dd,J＝10.8,2.9Hz,1H),6.88-6.82(m,1H),3.94(s,3H),3.72(s,3H)。LC-MA:m/z 313.0,315.0[M+H] ⁺ (esi+), rt=0.88 LCMS method M2.

Step 2:3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester

To a stirred solution of methyl 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylate (84%, 6.19g,16.6 mmol) and sodium iodide (12.55 g,83.1 mmol) in acetonitrile (120 mL) at 0 ℃ was added acetyl chloride (1.3 mL,18.3 mmol) dropwise. The reaction was then stirred at 0deg.C for 1h. The reaction was diluted with EtOAc (200 mL) and taken up in saturated Na ₂ CO ₃ Aqueous (200 mL) and saturated aqueous sodium sulfate (50 mL) were washed. The aqueous solution was extracted with EtOAc (2×200 mL), passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% etoac/heptane over silica (on a Biotage Sfar 100g column, using DCM to wet the supported compound) and concentrated in vacuo to give 3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester (84.0%) as a yellow solid (3.54 g, 44%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.35(s,1H),7.25(dd,J＝8.8,5.8Hz,1H),7.11(dd,J＝10.7,2.9Hz,1H),6.86-6.80(m,1H),3.91(s,3H),3.70(s,3H)。LC-MS：m/z 405.1[M+H] ⁺ (esi+), rt=0.91 LCMS squareMethod M2.

Step 3:3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylate (84%, 3.54g,7.36 mmol), cuprous iodide (2.11 g,11.0 mmol) and tetrabutylammonium iodide (1.09 g,2.94 mmol) in DMF (38 mL) was added methyl difluoro (fluorosulfonyl) acetate (4.7 mL,36.8 mmol) and stirred at 70℃for 4h. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3X 200 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo (high vacuum for removal of DMF). The compound was purified by FCC using 0-50% etoac/heptane over silica (on a Biotage Sfar 100g column, using DCM to wet the supported compound) and concentrated in vacuo to give methyl 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (93.0%) as a yellow solid (2.52 g,6.77mmol, 92%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.53(s,1H),7.33(dd,J＝8.9,5.8Hz,1H),7.16(dd,J＝10.7,2.9Hz,1H),6.87(ddd,J＝8.9,8.2,2.9Hz,1H),3.96(s,3H),3.72(s,3H)。m/z：347.0[M+H]+, (esi+), rt=0.95 LCMS procedure M2.

Step 4:3- (4-fluoro-2-methoxy-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a stirred solution of 2, 6-tetramethylpiperidine (0.68 mL,4.03 mmol) in anhydrous THF (24 mL) at 0deg.C was added dropwise butyllithium (2.5M/hexane) (1.1 mL,2.69 mmol) and stirred for 30min. The reaction was cooled to-78 ℃ and treated by dropwise addition of methyl 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (93%, 500mg,1.34 mmol) in anhydrous THF (5 mL) at-78 ℃ for 40 min and stirred at-78 ℃ for 30min. The reaction was cooled again to-78 ℃ and 1-iodopyrrolidine-2, 5-dione (336 mg,1.48 mmol) was added dropwise to anhydrous THF (5 mL) at-78 ℃ for 20min and stirred at this temperature for 30min. The reaction was quenched with saturated aqueous NH4Cl (2 mL) at-78 ℃ and allowed to warm to room temperature and stirred for 30min. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL), passed through a phase separator and concentrated in vacuo. The supported compound was wetted by FCC with 0-50% etoac/heptane over silica (on Biotage Sfar 10g column, DCM) The compound was purified and concentrated in vacuo to give 3- (4-fluoro-2-methoxy-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (82.0%) as an orange solid (216 mg,0.375mmol, 28%). ¹ H NMR(500MHz,DMSO-d ₆ )δ7.32(dd,J＝8.8,5.8Hz,1H),7.16(dd,J＝10.7,2.9Hz,1H),6.85(td,J＝8.5,2.9Hz,1H),4.02(s,3H),3.73(s,3H)。LC-MS：m/z 473.1[M+H] ⁺ (esi+), rt=1.03 LCMS method M2.

Step 5:3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a stirred solution of 3- (4-fluoro-2-methoxy-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (82%, 216mg,0.375 mmol) in anhydrous methanol (3.3 mL) was added dropwise 5.4M NaOMe/MeOH (0.069 mL,0.375 mmol) at 0 ℃. The reaction was then stirred at room temperature for 0.5h. The reaction was retreated with 5.4M NaOMe/MeOH (0.035 mL,0.188 mmol) at 0deg.C and stirred for 0.5h. The reaction was further reprocessed with 5.4M NaOMe/MeOH (0.017 mL,0.0938 mmol) and stirred at room temperature for 0.5 hours. The reaction was quenched with saturated NH4Cl (aq) (1 mL) and acidified to pH 1 using 2M HCl (aq). The reaction mixture was concentrated in vacuo, poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane followed by 0-80% meoh/EtOAc (on a Biotage Sfar5g cartridge, using DCM to wet the supported compound) and concentrated in vacuo to give methyl 3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylate (68.0%) as a pale yellow solid (148 mg,0.267mmol, 71%). LC-MS: m/z 377.1[ M+H ] ] ⁺ (esi+), rt=3.75 LCMS method 4.

Step 6:3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylic acid: to a mixture of methyl 3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylate (68%, 143mg,0.258 mmol) in THF (0.8 mL): water (0.2 mL) was added lithium hydroxide (12 mg,0.517 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 2M HCl (aq) to pH 1, poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases are passed through a phase separator and are in true senseConcentrating in the air. The compound was purified by FCC using 0-100% EtOAc/heptane followed by 0-60% meoh/EtOAc over silica (on a Biotage Sfar 5g cartridge, wet the supported compound with EtOAc) and concentrated in vacuo to give 3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylic acid (82.0%) as a pale yellow solid (71 mg,0.161mmol, 62%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.25(dd,J＝8.8,5.8Hz,1H),7.14(dd,J＝10.7,2.9Hz,1H),6.84(ddd,J＝8.9,8.2,2.9Hz,1H),4.17(s,3H),3.73(s,3H)。LC-MS：m/z 363.1[M+H] ⁺ (esi+), rt=3.03 LCMS method 4.

Step 7: (S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl alkylene) carbamate: to a stirred solution of 3- (4-fluoro-2-methyl-phenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxylic acid (82%, 95mg,0.225 mmol) in anhydrous DMF (1.0 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.079 mL,0.450 mmol) and HATU (103 mg,0.270 mmol) at room temperature followed by N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda in anhydrous DMF (0.5 mL) ⁶ -a sulfinyl group]Tert-butyl carbamate (79 mg,0.292 mmol). The reaction was stirred at room temperature for 18h. The reaction was poured into water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC first using 0-100% EtOAc/heptane over silica (on Biotage Sfar 5g column, using DCM to wet the supported compound), concentrated in vacuo, and then again using 0-100% DCM/heptane, followed by 0-100% EtOAc/DCM, and rinsing with 0-20% meoh/EtOAc over silica (on Biotage Sfar 10g column, using DCM to wet the supported compound) and concentrated in vacuo to give (S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) - λ) as a white solid ⁶ Tert-butyl (88.0%) of (74 mg,0.106mmol, 47%) sulfinyl) carbamate. ¹ H NMR(500MHz,DMSO-d ₆ )δ11.50(s,1H),8.35(s,1H),7.98-7.87(m,1H),7.77-7.65(m,2H),7.26(dd,J＝8.9,5.8Hz,1H),7.12(dd,J＝10.7,2.9Hz,1H),6.83(td,J＝8.5,2.9Hz,1H),4.18(s,3H),3.74(s,3H),3.39(s,3H),1.21(s,9H)。LC-MS：m/z 615.3[M+H] ⁺ (esi+), rt=0.84 LCMS procedure M2.

Step 8: (S) -3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: to (S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ To a stirred solution of tert-butyl (74 mg,0.120 mmol) of alkylene) carbamate in 1, 4-dioxane (0.5 mL) was added 4M HCl/dioxane (0.50 mL,2.00 mmol) and the reaction was stirred at room temperature for 4h. Saturated Na for reaction ₂ CO ₃ (aqueous) (2 mL) quench, pour into water (10 mL) and extract with EtOAc (3X 15 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane followed by 0-80% meoh/EtOAc over silica (on Biotage Sfar 5g cartridge, using DCM to wet the supported compound) and concentrated in vacuo. The compound was further purified by reverse phase FCC using 10-100% mecn+0.1% formic acid/water+0.1% formic acid (on a C18 Biotage Sfar 6g column, loaded with compound using a sample pre-loaded with MeOH solution) and concentrated in vacuo to give 3- (4-fluoro-2-methoxy-phenoxy) -5-methoxy-N- [3- (methylsulfonyl) phenyl as a white solid]-6- (trifluoromethyl) pyridazine-4-carboxamide (99.0%) (9.0 mg, 14%) and (S) -3- (4-fluoro-2-methoxyphenoxy) -5-methoxy-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (99.0%) as white solids (18 mg, 29%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.43(s,1H),8.33(t,J＝2.0Hz,1H),7.87(ddd,J＝8.0,2.2,1.1Hz,1H),7.73(dt,J＝8.0,1.3Hz,1H),7.64(t,J＝7.9Hz,1H),7.28(dd,J＝8.8,5.8Hz,1H),7.13(dd,J＝10.7,2.9Hz,1H),6.84(td,J＝8.5,2.9Hz,1H),4.28-4.23(m,1H),4.19(s,3H),3.74(s,3H),3.07(d,J＝1.0Hz,3H)。LC-MS：m/z 515.1[M+H] ⁺ (esi+), rt=3.06, lc-MS method 4.

Example 67

Compound 1518: (S) -5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) LiOH, THF/H ₂ O, room temperature; b) N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate, EDC, pyridine; c) Magnesium (ethyl) bromide (3M/Et) ₂ O)、THF，-78℃，NBS；d)DCM、TFA

Step 1:3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid

To a mixture of methyl 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (500 mg,1.44 mmol) in THF (4.5 mL): water (1 mL) was added lithium hydroxide (173 mg,7.22 mmol) and the mixture was stirred at room temperature for 1h. The reaction mixture was quenched with 2M HCl (aq) to pH 1, poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were separated and concentrated in vacuo to give 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (69.0%) as a pale yellow solid (509 mg, 73%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.47(s,1H),7.32(dd,J＝8.8,5.8Hz,1H),7.15(dd,J＝10.7,2.9Hz,1H),6.87(td,J＝8.5,2.9Hz,1H),3.71(s,3H)。LC_MS:m/z 333.0[M+H] ⁺ (esi+), rt=2.96 LCMS method 4.

Step 2: (S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide) phenyl) (methyl) (oxo) lambda ⁶ -t-butyl sulfinyl) carbamate: 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (100 mg,0.301 mmol), N- [ (S) - (3-aminophenyl) (methyl) oxo- λ ⁶ -a sulfinyl group]A mixture of tert-butyl carbamate (98 mg,0.361 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (69 mg,0.361 mmol) was dissolved in pyridine (2 mL) and stirred at room temperature for 2h. The reactant being N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (20 mg,0.072 mmol) was treated again and stirred at room temperature for 2h. The reactant is 3- (ethyliminomethyleneamino) -N, N-dimethyl-propyl-1-amine hydrochloride (14 mg,0.072 mmol) was treated again and stirred at room temperature for 3h. The reaction was poured into water (30 mL) and extracted with DCM (3×40 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo, purified by FCC over silica (on a Biotage Sfar 10g column, wet the supported compound with DCM) using 0-100% etoac in heptane and concentrated in vacuo to give (S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) - λ) as a pale yellow solid ⁶ Tert-butyl (95.0%) carbamate (175 mg,0.284mmol, 94%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.26(s,1H),8.64(s,1H),8.37-8.31(m,1H),8.03-7.95(m,1H),7.75-7.67(m,2H),7.37(dd,J＝8.8,5.9Hz,1H),7.15(dd,J＝10.7,2.9Hz,1H),6.88(td,J＝8.5,2.9Hz,1H),3.72(s,3H),3.40(s,3H),1.25(s,9H)。LC-MS：m/z585.2[M+H] ⁺ (esi+), rt=1.00 LCMS method M2.

Step 3: (S) - ((3- (5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate:

(S) - ((3- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda at-78 DEG C ⁶ To a stirred solution of tert-butyl (sulfanyl) carbamate (72 mg,0.123 mmol) in anhydrous THF (1.5 mL) was added magnesium (ethyl) bromide (3M in Et) ₂ O) (0.21 mL,0.616 mmol) and stirred for 2.5h. The reaction was quenched with magnesium (ethyl) bromide (3M in Et) ₂ O) (0.21 mL,0.616 mmol) was treated again and stirred at-78℃for 1h. The reaction was quenched with methanol (0.40 mL,9.85 mmol). NBS (39 mg,0.222 mmol) was then added to the reaction, allowed to warm to room temperature and stirred for 26h. The reaction was retreated with NBS (13 mg,0.073mmol,0.6 eq.) and stirred at room temperature for 15.5 hours. The reaction was retreated with NBS (13 mg,0.073mmol,0.6 eq.) and stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were separated and concentrated in vacuo. Compounds were purified by FCC using 0-100% EtOAc in heptane, silica-lined and rinsed with 0-20% MeOH in EtOAc (in Biotage Sfar5g column, wet the supported compound with DCM and concentrate in vacuo to give (S) - ((3- (5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) - λ) as a yellow oil ⁶ Tert-butyl (60.0%) sulfinyl) carbamate (66 mg, 52%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.41(s,1H),8.39(t,J＝2.0Hz,1H),7.93(dt,J＝6.8,2.2Hz,1H),7.76-7.70(m,2H),7.31(dd,J＝8.8,5.9Hz,1H),7.16(dd,J＝10.7,2.9Hz,1H),6.86(td,J＝8.5,2.9Hz,1H),3.75(s,3H),3.40(d,J＝1.4Hz,3H),2.85(q,J＝7.3Hz,2H),1.29-1.24(m,3H),1.23(s,9H)。m/z：613.3[M+H] ⁺ (esi+), rt=0.91 LCMS method M3.

Step 4: (S) -5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: to (S) - ((3- (5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ To a stirred solution of tert-butyl (sulfoanyl) carbamate (60%, 66mg,0.0646 mmol) in DCM (0.8 mL) was added TFA (0.048 mL,0.646 mmol) dropwise and stirred at room temperature for 2h. With saturated NaHCO ₃ The reaction was basified in water (2 mL), poured into water (10 mL) and extracted with DCM (3X 20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified by reverse phase using 10-100% mecn+0.1% formic acid/water+0.1% formic acid (on a Biotage Sfar C18 g column, compound loaded onto a sampler preloaded with a solution of compound in MeOH and dried in an oven at 40 ℃), concentrated in vacuo and freeze dried overnight to give (S) -5-ethyl-3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (90.0%) as a white solid (14 mg, 38%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.31(s,1H),8.36(t,J＝2.0Hz,1H),7.89-7.83(m,1H),7.77-7.69(m,1H),7.64(t,J＝7.9Hz,1H),7.32(dd,J＝8.9,5.8Hz,1H),7.15(dd,J＝10.7,2.9Hz,1H),6.86(td,J＝8.5,2.9Hz,1H),4.26(s,1H),3.74(s,3H),3.08(d,J＝1.1Hz,3H),2.84(q,J＝7.2Hz,2H),1.27(t,J＝7.5Hz,3H)。LC-MS：m/z 513.2 1[M+H]+, (esi+), rt=3.04 LCMS method 4.

Example 68

Compound 1519: (S) -5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) K (K) ₂ CO ₃ Acetonitrile, 70 ℃; b) Acetyl chloride, naI, acetonitrile; c) CuI, TBAI, methyl difluoro (fluorosulfonyl) acetate, DMF,70 ℃; d) THF, 2, 6-tetramethylpiperidine, n-dili (2.5M/hexane), -1-iodopyrrolidine-2, 5-dione at 78 ℃; e) Cyclopropylboronic acid, bis [3- (diphenylphosphino) cyclopenta-2, 4-dien-1-yl]Iron; dichloromethane; palladium dichloride, K ₂ CO ₃ ，100℃；f)LiOH、THF/H ₂ O, 20h at 40 ℃; g) Oxalyl chloride, N- [ (S) - (3-aminophenyl) (methyl) oxy- & lambda & lt/EN & gt ⁶ -a sulfinyl group]Tert-butyl carbamate, DIEA, DMF, room temperature; h) DCM, TFA

Step 1: 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester: a mixture of 4-fluoro-2-methyl-phenol (5.05 g,40.1 mmol), methyl 3, 6-dichloropyridazine-4-carboxylate (7.90 g,38.2 mmol) and dipotassium carbonate (7.91 g,57.2 mmol) in acetonitrile (79 mL) was stirred at 70℃for 14.5h. The reaction was cooled to room temperature, filtered and washed with DCM (2×100 mL) and concentrated in vacuo. The compound was purified by FCC using 0-50% etoac/heptane over silica (on a Biotage Sfar 350g column, using DCM to wet the supported compound) and concentrated in vacuo to give methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (9.12 g,20.9mmol, 55%) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27(s,1H),7.26-7.21(m,2H),7.16-7.07(m,1H),3.94(s,3H),2.11(s,3H)。LC-MS：m/z 297.0,299.0[M+H] ⁺ (esi+), rt=0.93 LCMS method M2.

Step 2:3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester: to a stirred solution of methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (3.00 g,10.1 mmol) and sodium iodide (15.16 g,0.101 mol) in anhydrous acetonitrile (34 mL) at 0 to 5℃was added dropwiseA solution of acetyl chloride (0.79 mL,11.1 mmol) in anhydrous acetonitrile (34 mL) was maintained for 30min. The reaction was then stirred at 5℃for 30min, followed by stirring at room temperature for 2h. The reaction was retreated with acetyl chloride (0.10 mL,1.41 mmol) at 0deg.C and stirred at room temperature for 2h. The reaction mixture was saturated with NaHCO ₃ The aqueous solution (20 mL) was diluted and stirred for 5min. Water (100 mL) was added and the resulting solution was extracted with EtOAc (3X 100 mL). The combined organic phases were washed with saturated aqueous sodium thiosulfate (2×50 ml), concentrated in vacuo via a phase separator and purified by FCC over silica (on a Biotage Sfar 200g column, loaded compound wet with DCM) using 0-100% etoac/heptane and concentrated in vacuo to give methyl 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylate (95.0%) as a pale yellow oil (2.19 g,5.36mmol, 53%). LC-MS: m/z 389.0[ M+H ]] ⁺ (esi+), rt=1.04 LCMS method M2.

Step 3:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylate (2.19 g,5.64 mmol), cuprous iodide (1.62 g,8.46 mmol) and tetrabutylammonium iodide (836 mg,2.26 mmol) in DMF (29.14 mL) was added methyl difluoro (fluorosulfonyl) acetate (3.6 mL,28.2 mmol) and stirred at 70℃for 4h. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3X 200 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo (high vacuum for removal of DMF). The compound was purified by FCC using 0-50% etoac/heptane over silica (on a Biotage Sfar 200g column, using DCM to wet the supported compound) and concentrated in vacuo to give methyl 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (76.0%) as a yellow solid (1.49 g,3.43mmol, 61%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.54(s,1H),7.34-7.24(m,2H),7.18-7.11(m,1H),3.97(s,3H),2.13(s,3H)。LC-MS：m/z 331.1[M+H] ⁺ (esi+), rt=0.98 LCMS method M2.

Step 4:3- (4-fluoro-2-methyl-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a stirred solution of 2, 6-tetramethylpiperidine (0.58 mL,3.45 mmol) in anhydrous THF (12 mL) at 0deg.C was added dropwise butyllithium (2.5M/hexane) (0.92 mL, 2). 30 mmol) and stirred for 30 minutes. The reaction was cooled to-78 ℃ and a pre-cooled mixture of 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (76%, 500mg,1.15 mmol) in anhydrous THF (12 mL) was transferred to the LiTMP mixture by cannula, both at-78 ℃. Immediately thereafter, a cooled mixture of 1-iodopyrrolidine-2, 5-dione (299 mg,1.15 mmol) in anhydrous THF (6 mL) was added at-78 ℃ and stirred at this temperature for 30 min. At room temperature with saturated NH ₄ The reaction was quenched with Cl (aqueous) (1 ml) and warmed to room temperature. The reaction was poured into water (30 mL), extracted with EtOAc (3×50 mL), the combined organic phases separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane over silica and rinsed with 0-60% meoh/EtOAc (on a Biotage Sfar 25g column, wet the supported compound with DCM) and concentrated in vacuo to give methyl 3- (4-fluoro-2-methyl-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylate (85.0%) as an orange solid (292 mg,0.637mmol, 55%). ¹ H NMR(500MHz,DMSO-d ₆ )δ7.32(dd,J＝9.0,5.0Hz,1H),7.26(dd,J＝9.4,3.1Hz,1H),7.15(td,J＝8.5,3.2Hz,1H),4.04(s,3H),2.10(s,3H)。LC-MS：m/z 457.0[M+H] ⁺ (esi+), rt=1.06 LCMS method M2.

Step 5: 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: 3- (4-fluoro-2-methyl-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (75%, 203mg, 0.336 mmol), cyclopropylboronic acid (34 mg,0.401 mmol), bis [3- (diphenylphosphino) cyclopenta-2, 4-dien-1-yl ]Iron; dichloromethane; a mixture of palladium dichloride (14 mg,0.0167 mmol) and dipotassium carbonate (92 mg,0.668 mmol) in 1, 4-dioxane (1.8 mL) water (0.2 mL) was degassed with nitrogen and heated to 100deg.C for 3h. The reactants being bis [3- (diphenylphosphino) cyclopenta-2, 4-dien-1-yl]Iron; dichloromethane; palladium dichloride (14 mg,0.0167 mmol) was reprocessed and degassed with nitrogen and stirred at 100℃for 1h. The reaction was run with cyclopropylboronic acid (34 mg,0.401 mmol), bis [3- (diphenylphosphino) cyclopenta-2, 4-dien-1-yl)]Iron; dichloromethane; palladium dichloride (14 mg,0.0167 mmol) and dipotassium carbonate (51 mg, 0.336 mmol) were reprocessed and degassed with nitrogen and stirred at 100℃for 4h. Allowing the reaction mixture to reactWarmed to room temperature, poured into water (20 mL) and extracted with DCM (3×20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified by FCC using 0-100% EtOAc/heptane over silica and rinsing with 0-60% meoh/EtOAc (on a Biotage Sfar 10g column, wet the supported compound with DCM) and concentrated in vacuo to give methyl 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (81.0%) as a yellow viscous oil (114 mg,0.249mmol, 75%). ¹ H NMR(500MHz,DMSO-d ₆ -)δ7.28-7.22(m,2H),7.13(td,J＝8.5,3.5Hz,1H),4.00(s,3H),2.18-2.12(m,1H),2.08(s,3H),1.12-1.06(m,2H),0.82-0.75(m,2H)。LC-MS：m/z 371.2[M+H] ⁺ (esi+), rt=1.04 LCMS method M2.

Step 6: 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid: to a mixture of methyl 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (113 mg,0.305 mmol) in THF (1 mL): water (0.25 mL) was added lithium hydroxide (15 mg,0.610 mmol) and the mixture was stirred at room temperature for 16h. The reaction was treated again with LiOH (29 mg,1.22 mmol) and stirred at room temperature for 1h. The reaction was treated again with LiOH (29 mg,1.22 mmol) and stirred at room temperature for 16h. The reaction was treated again with LiOH (29 mg,1.22 mmol) and stirred at 40℃for 20h. The reaction was treated again with LiOH (29 mg,1.22 mmol) and stirred at 60℃for 6.5h. The reaction was treated again with lithium hydroxide (29 mg,1.22 mmol) and stirred at 40℃for 3h. The reaction mixture was acidified to pH 1 with 2M HCl (aqueous), poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane followed by 0-80% meoh/EtOAc over silica (on a Biotage Sfar 5g cartridge, wet the supported compound with EtOAc) and concentrated in vacuo to give 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (62 mg,0.174mmol, 57%) as an orange solid. LC-MS: m/z 357.2[ M+H ] ] ⁺ (esi+), rt=0.74 LCMS method M2.

Step 7: n- [ (S) - {3- [ 5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-yl ] amino]Phenyl } (methyl) oxo groups-λ ⁶ -a sulfinyl group]T-butyl carbamate: to a stirred solution of 5-cyclopropyl-3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (92%, 52mg,0.134 mmol) in DCM (0.6 mL) was added N, N-dimethylformamide (2.1 uL,0.0269 mmol) followed by oxalyl chloride (13 uL,0.148 mmol) under nitrogen and at room temperature. The reaction was stirred for 1h. N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda subsequently added to DCM (0.2 mL) ⁶ -a sulfinyl group]Tert-butyl carbamate (44 mg,0.161 mmol) was then added DIEA (47 ul, 0.264 mmol) and the reaction stirred at room temperature for 1.5h. Water (2 mL) was added to the reaction and the reaction mixture was passed through a phase separator and rinsed with DCM (3X 3 mL). The combined organic phases were combined, concentrated in vacuo, and the compound was purified by FCC using 0-100% EtOAc/heptane over silica and rinsed with 0-60% meoh/EtOAc (on a Biotage Sfar 5g column, wet the supported compound with DCM) and concentrated in vacuo to give N- [ (S) - {3- [ 5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-amid-yl as a white viscous solid ]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (94.0%) (79 mg,0.122mmol, 91%). m/z:509.1[ M-Boc+H] ⁺ (esi+), rt=0.99 LCMS method M2.

Step 8: (S) -5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: to N- [ (S) - {3- [ 5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-carboxamido]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]To a stirred solution of tert-butyl carbamate (94%, 79mg,0.122 mmol) in DCM (1.5 mL) was added dropwise TFA (0.091 mL,1.22 mmol) and stirred at room temperature for 3h. Saturated NaHCO for reaction ₃ The aqueous solution (2 mL) was acidified, poured into water (10 mL) and extracted with DCM (3X 20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified over silica (on a Biotage Sfar 5g column using DCM wet load compound) using 0-100% etoac/heptane, concentrated in vacuo and lyophilized overnight in 1:1 mecn/water to give (S) -5-cyclopropyl-3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonimidoyl) phenyl) -6- (trifluoromethyl) pyridazine as a white solid-4-carboxamide (95.0%) (28 mg, 42%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.21(s,1H),8.29(t,J＝2.0Hz,1H),7.93-7.84(m,1H),7.73(d,J＝7.8Hz,1H),7.64(t,J＝7.9Hz,1H),7.29-7.21(m,2H),7.13(td,J＝8.5,3.2Hz,1H),4.26(s,1H),3.12-3.03(m,3H),2.23-2.16(m,1H),2.11(s,3H),1.10-1.02(m,2H),0.99-0.91(m,2H)。LC-MS：m/z 509.1[M+H] ⁺ (esi+), rt=3.11 LCMS method 4.

Example 69

Compound 1520: (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -5-phenyl-6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 1519 using appropriate reagents. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.06(s,1H),8.03(t,J＝2.0Hz,1H),7.67-7.61(m,1H),7.60 -7.55(m,1H),7.53(d,J＝7.7Hz,1H),7.51-7.44(m,5H),7.34(dd,J＝8.9,5.0Hz,1H),7.28(dd,J＝9.4,3.2Hz,1H),7.18(td,J＝8.7,3.3Hz,1H),4.21(s,1H),3.04-2.95(m,3H),2.19(s,3H)。m/z：545.3[M+H] ⁺ (esi+), rt=3.37 LCMS method 4.

Compound 1521: (S) -3- (4-fluoro-2-methylphenoxy) -5- (1-methyl-1H-pyrazol-4-yl) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 1519 using appropriate reagents. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.20(s,1H),8.17(t,J＝2.0Hz,1H),8.06(s,1H),7.74-7.67(m,2H),7.65(s,1H),7.58(t,J＝7.9Hz,1H),7.31(dd,J＝8.9,5.0Hz,1H),7.26(dd,J＝9.4,3.2Hz,1H),7.16(td,J＝8.6,3.2Hz,1H),4.24(s,1H),3.89(s,3H),3.05(s,3H),2.15(s,3H)。m/z：549.3[M+H] ⁺ (esi+), rt=2.88 LCMS method 4。

Example 70

Compound 1522: (S) -5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Cyclopropylamine, DIEA, acetonitrile, 50 ℃; b) LiOH, THF/H ₂ O, room temperature; c) TCFH, 1-methylimidazole, acetonitrile, N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate, room temperature; c) DCM, TFA, room temperature.

Step 1:5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: a mixture containing 3- (4-fluoro-2-methyl-phenoxy) -5-iodo-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (75%, 203mg,0.334 mmol), N-ethyl-N- (propan-2-yl) propan-2-amine (87 uL,0.501 mmol) and cyclopropylamine (35 uL,0.501 mmol) in anhydrous acetonitrile (2 mL) was stirred at 50℃for 3.5h. The reaction was combined with the experiment from vacuum concentration and the compound was purified by FCC using 0-100% EtOAc/heptane over silica and rinsed with 0-60% meoh/EtOAc (on a Biotage Sfar 5g column, wet the supported compound with DCM) and concentrated in vacuo to give methyl 5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (75.0%) as an orange solid (182 mg,0.354mmol, 106%). ¹ H NMR(500MHz,DMSO-d ₆ )δ7.31-7.25(m,1H),7.22-7.15(m,2H),7.08(td,J＝8.5,3.2Hz,1H),3.91(s,3H),2.57-2.52(m,1H),2.07(s,3H),0.79-0.73(m,2H),0.68-0.62(m,2H)。LC-MS：m/z 386.2[M+H]+, (esi+), rt=1.00 LCMS procedure M2.

Step 2:5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid: to a mixture of methyl 5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (75%, 182mg,0.354 mmol) in THF (1 mL): water (0.3 mL) was added lithium hydroxide (17 mg,0.709 mmol) and the mixture was stirred at room temperature for 65h. The reaction mixture was quenched with 2M HCl (aq) to pH1, poured into water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane followed by 0-80% meoh/EtOAc over silica (on a Biotage Sfar 5g cartridge, wet the supported compound with EtOAc) and concentrated in vacuo to give 5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (86.0%) as a pale yellow viscous oil (164 mg,0.380mmol, 107%). LC-MS: m/z 372.2[ m+h ] +, (esi+), rt=0.78 LCMS method M2.

Step 3: n- [ (S) - {3- [5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-carboxamido-e]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]T-butyl carbamate: to 5- (cyclopropylamino) -3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (78 mg,0.210 mmol), N- [ (S) - (3-aminophenyl) (methyl) oxo- λ ⁶ -a sulfinyl group]To a stirred solution of tert-butyl carbamate (74 mg, 0.275 mmol) and 1-methylimidazole (NMI) (59 uL,0.735 mmol) in anhydrous acetonitrile (0.5528 mL) was added N- [ chloro (dimethylamino) methylene in one portion]N-methyl ammonium hexafluorophosphate (TCFH) (71 mg,0.252 mmol) and the reaction was stirred at room temperature for 15.5h. The reaction was quenched with 1-methylimidazole (NMI) (59 uL,0.735 mmol) and N- [ chloro (dimethylamino) methylene]N-methyl ammonium hexafluorophosphate (TCFH) (71 mg,0.252 mmol) was treated again and stirred at room temperature for 24h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3X 20 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc/heptane and rinsed with 0-60% meoh/EtOAc (on a Biotage Sfar 5g column, using DCM and a few drops of EtOAc wet the supported compound) and concentrated in vacuo to give N- [ (S) - {3- [5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-amido ] as pale yellow color ]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (138 mg,0.153mmol, 73%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.23(s,1H),8.38-8.32(m,1H),7.96-7.86(m,1H),7.70-7.62(m,2H),7.23-7.13(m,2H),7.13-7.03(m,2H),3.36(s,3H),2.68-2.65(m,1H),2.09(s,3H),1.17(s,9H),0.74-0.69(m,2H),0.63-0.54(m,2H)。m/z：624.2 1[M+H] ⁺ (esi+), rt=0.93 LCMS method M2.

Step 4: (S) -5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide: to N- [ (S) - {3- [5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazin-4-carboxamido]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]To a stirred solution of tert-butyl carbamate (69%, 138mg,0.153 mmol) in DCM (2.7 mL) was added dropwise TFA (0.11 mL,1.53 mmol) and stirred at room temperature for 3h. Saturated NaHCO for reaction ₃ The aqueous solution (2 mL) was basified, poured into water (10 mL) and extracted with DCM (3X 20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified by silica (on a Biotage Sfar 5g column using DCM to wet the supported compound) using 0-100% etoac/heptane and concentrated in vacuo. The compound was further purified by reverse phase FCC using 10-100% mecn+0.1% formic acid/water+0.1% formic acid (on a C18Biotage Sfar 6g column, compound loaded onto a sampler preloaded with a solution of compound in MeOH), concentrated in vacuo and freeze dried overnight to give (S) -5- (cyclopropylamino) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (100.0%) as a white solid (44 mg,0.0840mmol, 55%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.13(s,1H),8.33(t,J＝1.9Hz,1H),7.87(ddd,J＝8.0,2.2,1.1Hz,1H),7.70-7.64(m,1H),7.59(t,J＝7.9Hz,1H),7.23-7.14(m,2H),7.13-7.03(m,2H),4.22(d,J＝1.3Hz,1H),3.05(d,J＝1.0Hz,3H),2.73-2.66(m,1H),2.10(s,3H),0.75-0.68(m,2H),0.66-0.58(m,2H)。LC-MS：m/z 524.1[M+H] ⁺ (esi+), rt=2.79 LCMS method 4.

The following compounds were synthesized in the same manner as described above.

Compound 1523: (S) -5- (azetidin-3-ylamino) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.21(s,1H),8.35(t,J＝2.0Hz,1H),7.94-7.85(m,1H),7.75-7.67(m,1H),7.63(t,J＝7.9Hz,1H),7.23-7.12(m,2H),7.08(td,J＝8.5,3.1Hz,1H),4.56-4.44(m,1H),4.27(s,1H),3.68-3.58(m,2H),3.49-3.41(m,2H),3.07(s,3H),2.08(s,3H)。m/z：539.2[M+H] ⁺ (esi+), rt=1.71 LCMS method 4.

Compound 1524: (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -5-morpholino-6- (trifluoromethyl) pyridazine-4-carboxamide

Example 71

Compound 1525:3- (4-cyano-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy- λ ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) K (K) ₂ CO ₃ Acetonitrile, 70 ℃; b) LiOH, THF/H ₂ O, room temperature; c) (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate, HATU, DIEA, DMF, room temperature; d) TFA, DCM.

Step 1:3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: 4-hydroxy-3-methylbenzonitrile (650 mg,4.88 mmol), 3-chloro-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (94%, 1.20g,4.43 mmol) and K ₂ CO ₃ A mixture of (920 mg,6.66 mmol) in acetonitrile (11.5 mL) was stirred at 70℃for 17h. The reaction was cooled to room temperature, filtered and washed with EtOAc (60 mL). The filtrate was washed with water (60 mL) and brine (60 mL), the organics separated, passed through a phase separator and concentrated in vacuo to give 3- (4-cyano-2-methyl-phenoxy) -5-methyl-bolo as an off-white powder 6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (90.0%) (1.68 g,4.30mmol, 97%). ¹ H NMR(500MHz,DMSO-d ₆ )δ7.94(d,J＝1.5Hz,1H),7.82(dd,J＝8.4,2.1Hz,1H),7.50(d,J＝8.4Hz,1H),4.02(s,3H),2.51-2.47(m,16H),2.16(s,3H)。m/z：352.1[M-BOC+H] ⁺ (esi+), rt=0.94 LCMS method 2.

Step 2:3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid: to a solution of 3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (90%, 1.68g,4.30 mmol) in THF (15 mL): water (3 mL) was added lithium hydroxide (236 mg,9.46 mmol), and the mixture was stirred at room temperature for 18h. The reaction was diluted with EtOAc and the product was extracted with water (×3). The pH of the aqueous phase was adjusted to 1 by dropwise addition of 1M HCl (aqueous). The aqueous layer was then extracted with EtOAc (3 times), dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (99.0%) as an off-white solid (1.48 g, 100%). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 7.95-7.91 (m, 1H), 7.81 (dd, j=8.4, 2.1hz, 1H), 7.47 (d, j=8.4 hz, 1H), 2.51-2.47 (m, 3H, overlapping DMSO peaks), 2.16 (s, 3H). m/z:338.1[ M+H ]] ⁺ (esi+), rt=2.67 LCMS method 4.

Step 3: n- [ (S) - {3- [3- (4-cyano-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazin-4-carboxamide]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]T-butyl carbamate: to a solution of intermediate 3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid (740 mg,2.19 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.77 mL,4.41 mmol) in anhydrous DMF (15 mL) was added N- [ (dimethylamino) (3H- [1,2, 3) ]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-N-methyl ammonium hexafluorophosphate (1000 mg,2.63 mmol). Subsequent addition of (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl sulfinyl) carbamate (98%, 787mg,2.85 mmol) and the mixture was stirred at room temperature for 18h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (3×50 mL). The organics were dried (MgSO ₄ ) Filtering and concentrating to obtain N- [ [3- [ [3- (4-cyano-2-methyl-phenoxy) as brown oilPhenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl]Amino group]Phenyl group]-methyl-oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (48.0%) (1.95 g, 72%). This material was used in the next reaction without further purification. ¹ H NMR(500MHz,DMSO-d ₆ )δ11.44(s,1H),8.40-8.36(m,1H),7.95-7.87(m,2H),7.85-7.80(m,1H),7.78-7.69(m,2H),7.50(d,J＝8.4Hz,1H),3.40(s,3H),2.69(s,3H),2.17(s,3H),1.22(s,9H)。m/z：490.1[M-BOC+H] ⁺ (esi+), rt=0.91 LCMS method 2.

Step 4:3- (4-cyano-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy- λ ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide: to N- [ (S) - {3- [3- (4-cyano-2-methylphenoxy) -5-methyl-6- (trifluoromethyl) pyridazin-4-carboxamido]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]To a solution of tert-butyl carbamate (48%, 1.95g,1.59 mmol) in DCM (12 mL) was added 2, 2-trifluoroacetic acid (2.4 mL,32.3 mmol). The mixture was stirred at room temperature for 4h. Saturated NaHCO used for reaction ₃ Dilute, extract with DCM (3 times), dry (MgSO ₄ ) Filtered and concentrated to a yellow oil. By basicity (0.1% NH) ₃ ) Reverse phase chromatography (Sfar C18 60g D Duo 30, 10-40% MeCN/H ₂ O, combined fractions 14 to 16), evaporated and freeze dried over the weekend to give 3- (4-cyano-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy-lambda as an off-white powder ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide (141 mg,0.282mmol, 18%). The impure eluate was evaporated to a yellow oil (471 mg) and further purified by preparation 1. The earlier obtained material and the material obtained from preparation 1 were combined and freeze-dried overnight to give 3- (4-cyano-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy- λ as a white powder ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide (463 mg, 60%). ¹ H NMR(400MHz,CD ₃ OD)δ8.44(t,J＝1.9Hz,1H),7.98-7.94(m,1H),7.87-7.82(m,1H),7.77-7.73(m,1H),7.71-7.64(m,2H),7.43(d,J＝8.4Hz,1H),3.17(s,3H),2.62-2.59(m,3H),2.23(s,3H)。m/z：490.2[M+H] ⁺ (esi+), rt=2.80 LCMS squareMethod 4.

Example 72

Compound 1526:3- (4-cyano-2-methylphenoxy) -N- {3- [ (R) -imino (meth) oxy- λ ⁶ Thio group]Phenyl } -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a similar reaction sequence as described for compound xx using 3- (4-cyano-2-methyl-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxylic acid and N- [ (R) - (3-aminophenyl) (methyl) oxo- λ ⁶ -a sulfinyl group]Tert-butyl carbamate. ¹ H NMR(500MHz,CD ₃ OD) δ8.44 (t, j=1.9 hz, 1H), 7.98-7.93 (m, 1H), 7.86-7.82 (m, 1H), 7.77-7.73 (m, 1H), 7.71-7.64 (m, 2H), 7.43 (d, j=8.4 hz, 1H), 3.17 (s, 3H, and CD ₃ OD satellite overlap), 2.63-2.58 (m, 3H), 2.23 (s, 3H). m/z:490.2[ M+H ]] ⁺ (esi+), rt=2.80 LCMS method 4.

EXAMPLE 73

Compound 1527:3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- (1-oxopyridin-1-ium-3-yl) pyridazine-4-carboxamide

Reagents and conditions: 1-oxo-radical pyridin-1-ium-3-amine hydrochloride, HATU, DIEA, DMF; b) 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile, 2M Na ₂ CO ₃ 1, 4-dioxane, pd (dppf) Cl ₂ 。

Step 1:3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- (1-oxopyridin-1-ium-3-yl) pyridazine-4-carboxamide: to a mixture of 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid (64 mg,0.156 mmol), HATU (71 mg,0.187 mmol), DIEA (0.082 mL,0.467 mmol) in DMF (1.5 mL) was added 1-oxolanidin-1-ium-3-amine; the hydrochloride salt (25 mg,0.171 mmol). The reaction mixture was stirred at 40 ℃ for 3h, then at room temperature overnight. LCMS analysis indicated reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (3×5 mL) and brine (5 mL). Dried (MgSO 4), filtered and concentrated to give an orange oil. The residue was purified by FCC (5 g,0 to 100% meoh/EA) to give 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- (1-oxopyridin-1-ium-3-yl) pyridazine-4-carboxamide (80.0%) as an orange solid (32 mg, 33%). m/z:504.0[ M+H ] ] ⁺ (esi+), rt=0.62 min LCMS method 2.

Step 2:3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- (1-oxopyridin-1-ium-3-yl) pyridazine-4-carboxamide: 2M Na ₂ CO ₃ (2M aqueous solution) (170 uL,0.340 mmol) was added to 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile (29 mg,0.115 mmol), 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl]Pyridazine-4-carboxamide (50 mg,0.0888 mmol) and Pd (dppf) Cl ₂ (6.5 mg, 8.88. Mu. Mol) in 1, 4-dioxane (2 mL). The mixture was degassed with nitrogen for 5 minutes and then heated at 90 ℃ for 6 hours. LCMS analysis indicated reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organics were dried (MgSO ₄ ) Filtration and concentration gave a brown oil. Purification by preparative HPLC (standard method) afforded 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-N- (1-oxopyridin-1-ium-3-yl) pyridazine-4-carboxamide (99.0%) as a white solid (10 mg, 18%). ¹ H NMR(500MHz,CD ₃ OD)δ9.06(t,J＝1.9Hz,1H),8.18(m,1H),7.95-7.89(m,2H),7.81-7.73(m,3H),7.57(dd,J＝8.6,6.4Hz,1H),7.53(d,J＝1.6Hz,1H),7.49-7.41(m,2H),3.82(s,3H),2.41(s,3H)。m/z：479.2[M+H] ⁺ (esi+), rt=2.36 LCMS method 4.

Example 74

Compound 1528:3- (4-cyano-2-methoxyphenoxy) -6- (2, 2-difluorocyclopropyl) -N- {3- [ (S) -imino (meth) oxy-, - λ ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide

Reagents and conditions: a) (2, 2-Difluorocyclopropyl) -trifluoro-potassium borate, pd Amphos, 2M Na ₂ CO ₃ 1, 4-dioxane, 100 ℃; b) 1M sodium trimethylsilane, THF; c) (S) -tert-butyl N- [ (3-aminophenyl) -methyl-oxo-lambda ⁶ -a sulfinyl group]、HATU、DIEA、DMF，rt；d)TFA、DCM，rt

Step 1:3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester: 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (250 mg,0.588 mmol), (2, 2-difluorocyclopropyl) -trifluoro-boric acid potassium salt (130 mg,0.706 mmol) and 2M disodium carbonate (882ul, 1.76 mmol) were degassed with nitrogen in 1, 4-dioxane (2 mL). Pd Amphos (42 mg,0.0588 mmol) was added and the solution heated at 100deg.C for 3 days. No additional borate is available for treatment. The solution was cooled and the material purified using FCC (10 g silica, 0-100% EtOAc/heptane; direct loading of the reaction mixture). The clean solvent was evaporated in vacuo to give 3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester (45 mg,0.120mmol, 20%) as an off-white solid. m/z:376.2[ M+H ]] ⁺ (esi+), rt=0.87 min LCMS method 2.

Step 2:3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid: to a solution of 3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester (35 mg,0.0933 mmol) in anhydrous THF (3 mL) was added 1M sodium trimethylsilane (140 ul,0.140 mmol) and the solution was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo to give 3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid (75.0%) as a brown solid (45 mg,0.0934mmol, 100%). The material was used in the next step without further purification. m/z:362.1[ M+H ]] ⁺ (esi+), rt=0.61 min LCMS method 2.

Step 3: n- [ (S) - {3- [3- (4-cyano-2-methoxy)Phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methylpyridazine-4-amid-yl]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]T-butyl carbamate: 3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carboxylic acid (45 mg,0.125 mmol), (S) -N- [ (3-aminophenyl) -methyl-oxo- λ ⁶ -a sulfinyl group]A mixture of tert-butyl carbamate (22 mg,0.0830 mmol), HATU (35 mg,0.0913 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.032 mL, 0.183mmol) in anhydrous DMF (3.3672 mL) was stirred at ambient temperature for 4h. IPC indicates the formation of the desired product. The mixture was purified directly using FCC (0-100% EtOAc, followed by 0-20% MeOH/DCM,10g silica). The clean solvent was evaporated in vacuo to give N- [ (S) - {3- [3- (4-cyano-2-methoxyphenoxy) -6- (2, 2-difluorocyclopropyl) -5-methylpyridazine-4-amid-yl as a white solid ]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (11 mg,0.0142mmol, 11%). m/z:614.2[ M+H ]] ⁺ (esi+), rt=0.87 min LCMS method 2.

Step 4 3- (4-cyano-2-methoxyphenoxy) -6- (2, 2-difluorocyclopropyl) -N- {3- [ (S) -imino (meth) oxy- ] -lambda ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide: to N- [ [3- [ [3- (4-cyano-2-methoxy-phenoxy) -6- (2, 2-difluorocyclopropyl) -5-methyl-pyridazine-4-carbonyl]Amino group]Phenyl group]-methyl-oxo-lambda ⁶ -a sulfinyl group]To a solution of tert-butyl carbamate (11 mg,0.0179 mmol) in DCM (0.2423 mL) was added TFA (0.2423 mL) and the solution stirred at ambient temperature for 4h. IPC indicates the formation of the desired product. The solvent was removed under a stream of nitrogen. Saturated aqueous sodium carbonate (1 mL) was added and the solution extracted with DCM (3×1 mL). The combined organics were again washed with saturated sodium carbonate, passed through a phase separated frit, and the solvent removed in vacuo to give a crude solid. Purification was attempted using an inverse standard acidic gradient. The compound eluted approximately 90% pure. Purification was performed using standard FCC (10 g of silica; 0-100% EtOAc in heptane followed by 0-30% MeOH in DCM eluting the title compound and impurity approximately 10% MeOH). The solvent was removed in vacuo and the solid was freeze-dried to give 3 3- (4-cyano-2-methoxyphenoxy) -6- (2, 2-difluorocyclopropyl) -N- {3- [ (S) -imino (methyl) oxo as an off-white solid Radical-lambda ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide (90.0%) (8.3 mg,0.0145mmol, 81%). ¹ H NMR(500MHz,CD ₃ OD)δ8.47-8.43(m,1H),7.98-7.93(m,1H),7.82(ddd,J＝7.9,1.8,1.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.50(s,1H),7.43-7.39(m,2H),3.79(s,3H),3.26-3.21(m,1H),3.17(s,3H),2.52(s,3H),2.48-2.39(m,1H),2.04-1.97(m,1H)。m/z：514.2[M+H]+, (esi+), rt=2.57 LCMS method 4.

Example 75

Compound 1529:3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (R) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (4-methylphenyl) pyridazine-4-carboxamide

Reagents and conditions: a) Pd (dppf) Cl ₂ DCM, (4-methylphenyl) boric acid, 2M Na ₂ CO ₃ 1, 4-dioxane, 80 ℃; b) LiOH, THF/H ₂ O, room temperature; ) N- [ (R) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate, HATU, DIEA, DMF; d) 4M HCl/dioxane, 1, -4-dioxane, room temperature.

Step 1:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid methyl ester: 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (1:1) (0.17 g,0.235 mmol) was added to a stirred and N2 degassed solution of 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (1.00 g,2.35 mmol), (4-methylphenyl) boronic acid (0.64 g,4.70 mmol) and 2M disodium carbonate (2M aqueous solution) (3.5 mL,7.06 mmol) in 1, 4-dioxane (12 mL). The reaction mixture was stirred in a pressure flask at 80 ℃ for 2h. LCMS analysis indicated reaction was complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL) and brine (15 mL). The organics were dried (MgSO 4), filtered and concentrated to give a brown solid. Purification by FCC (25 g,0 to 40% ea/heptane) afforded 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid methyl ester (77.0%) as a pale yellow solid (1.20 g, 100%). LCMS (liquid crystal ms) ¹ H-NMR analysis indicated that this was the desired product with excess tolylboronic acid. Which is used directly in the next step.

Step 2:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid: to a solution of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid methyl ester (0.92 g,2.35 mmol) in THF (6 mL): water (2 mL) was added lithium hydroxide (0.13 g,5.17 mmol), and the mixture was stirred at room temperature for 18h. LCMS analysis indicated approximately 50% conversion. Additional lithium hydroxide (0.13 g,5.17 mmol) in water (2 mL) was added and the mixture was stirred at room temperature for 18h. LCMS analysis indicated approximately 75% conversion with 18% formamide at 215 nm. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×15 mL). The organics were concentrated to give a yellow semi-solid, 565mg. The pH was then adjusted to 1 by dropwise addition of 2M HCl (aqueous solution), and the aqueous layer was extracted with EtOAc (2×15 mL) and the organics concentrated to give 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid (93.0%) as a white solid (0.69 g, 73%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.72(d,J＝1.8Hz,1H),7.53(dd,J＝8.2,1.8Hz,1H),7.49-7.40(m,3H),7.32(d,J＝7.9Hz,2H),3.79(s,3H),2.38(s,3H),2.30(s,3H)。m/z：376.2[M+H] ⁺ (esi+), rt=0.71 min LCMS method 2.

Step 3: n- [ (R) - {3- [3- (4-cyano-2-methoxyphenoxy) -5-methyl-6- (4-methylphenyl) pyridazin-4-carboxamide ]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]T-butyl carbamate:

to a solution of 3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxylic acid (0.65 g,1.73 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.60 mL,3.46 mmol) in anhydrous DMF (7 mL) was added N- [ (dimethylamino) (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]N-methyl ammonium hexafluorophosphate (0.79 g,2.08 mmol). The mixture was stirred at room temperature for 5 minutes, after which N- [ (R) - (3-aminophenyl) (methyl) oxo- λ was added ⁶ -a sulfinyl group]A solution of tert-butyl carbamate (0.51 g,1.90 mmol) in anhydrous DMF (4 mL). The mixture was stirred at room temperature for 18h. LCMS analysis indicated reactionMost of this is done. The mixture was diluted with ethyl acetate (30 mL) and washed with water (3×15 mL) and brine (15 mL). The organics were dried (MgSO ₄ ) Filtered and concentrated to give a yellow foam. Purification by FCC (25 g,0 to 100% EA/heptane) afforded N- [ (R) - {3- [3- (4-cyano-2-methoxyphenoxy) -5-methyl-6- (4-methylphenyl) pyridazin-4-ylamino) as a pale yellow foam]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (90.0%) (0.90 g, 74%). ¹ H NMR(400MHz,CD ₃ OD)δ8.49(t,J＝2.0Hz,1H),8.02-7.95(m,1H),7.78(m,1H),7.70(t,J＝8.0Hz,1H),7.51(m,1H),7.47-7.39(m,4H),7.36(d,J＝8.0Hz,2H),3.83(s,3H),3.35(s,3H),2.43(s,3H),2.40(s,3H),1.27(s,9H)。m/z：628.2[M+H] ⁺ (esi+), rt=0.94 min LCMS method 2.

Step 4:3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (R) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (4-methylphenyl) pyridazine-4-carboxamide: to N- [ (R) - {3- [3- (4-cyano-2-methoxyphenoxy) -5-methyl-6- (4-methylphenyl) pyridazin-4-carboxamido]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]To a solution of tert-butyl carbamate (898 mg,1.43 mmol) in anhydrous 1, 4-dioxane (8 mL) was added 4M hydrogen chloride 4M to dioxane (18 mL,71.5 mmol). The mixture was stirred at room temperature for 2h. LCMS analysis indicated reaction was complete. The mixture was cooled to 0deg.C, diluted with ethyl acetate (20 mL) and saturated NaHCO ₃ The pH was adjusted to about 9. Ethyl acetate was extracted with (3×30 mL) and the organics were dried (MgSO ₄ ) Filtration and concentration gave an orange solid. By acid (0.1% formic acid) reverse phase chromatography (Sfar C18 30g D Duo,10%MeCN/H ₂ O 2CV 10-25％MeCN/H ₂ O 2CV，25-40％MeCN/H ₂ O 12CV，40％MeCN/H ₂ O 8CV THEN6 CV) to give a white solid (about 480 mg) which was dissolved in MeCN (20 mL) and purged with Si TMT (TCI chemical, 0.5mmol/g,1.41 g) at room temperature for 30min. The mixture was filtered and concentrated, followed by freeze-drying to give 3- (4-cyano-2-methoxyphenoxy) as a white solid Phenyl) -N- {3- [ (R) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (4-methylphenyl) pyridazine-4-carboxamide (100.0%) (435 mg, 58%). ¹ H NMR(500MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),7.97(m,1H),7.83(m,1H),7.65(t,J＝8.0Hz,1H),7.51(d,J＝1.6Hz,1H),7.47-7.39(m,4H),7.36(d,J＝7.8Hz,2H),3.83(s,3H),3.17(s,3H),2.43(s,3H),2.41(s,3H)。m/z：528.2[M+H] ⁺ (esi+), rt=2.88 LCMS method 4.

Example 76

Compound 1530:3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (S) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5-methyl-6- (4-methylphenyl) pyridazine-4-carboxamide

A method similar to the above method was used, but using N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate produces the title compound. This route gives 3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (S) -imino (meth) oxy-lambda as a white solid ⁶ Thio group]Phenyl } -5-methyl-6- (4-methylphenyl) pyridazine-4-carboxamide (0.52 g,0.984 mmol)

¹ H NMR(400MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),8.01-7.93(m,1H),7.83(m,1H),7.65(t,J＝8.0Hz,1H),7.51(m,1H),7.47-7.40(m,4H),7.36(d,J＝8.0Hz,2H),3.83(s,3H),3.17(s,3H),2.43(s,3H),2.41(s,3H)。m/z：528.2[M+H] ⁺ (esi+), rt=2.88 LCMS method 4.

Example 77

Compound 1531: (R) -3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide

Reagents and conditions: a) Pd (dppf) Cl ₂ .DCM、(4-cyanophenyl) boronic acid, 2M Na ₂ CO ₃ 1, 4-dioxane, 80 ℃; b) LiOH, THF/H ₂ O, room temperature; c) N- [ (R) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate, HATU, DIEA, DMF, d) 4M HCl/dioxane, 2-propanol, 1, 4-dioxane.

Step 1:3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester: pd (dppf) Cl ₂ DCM (1:1) (172 mg,0.235 mmol) was added to 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-pyridazine-4-carboxylic acid methyl ester (1000 mg,2.35 mmol), (4-cyanophenyl) boronic acid (691 mg,4.70 mmol) and 2M disodium carbonate (2M aqueous solution) (3.5 mL,7.06 mmol) in 1, 4-dioxane (40 mL) under stirring and N ₂ In the degassed solution. The reaction mixture was stirred at 80℃for 4h. The reaction mixture was diluted with EtOAc (about 80 mL) and washed with water (about 20 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. By FCC (Biotage isolera, siO ₂ Purification by gradient elution of 10-100% EtOAc in heptane) afforded 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester (92.0%) as an off-white solid (891 mg, 87%). ¹ H NMR(400MHz,CDCl ₃ )δ7.82(dd,J＝16.0,8.2Hz,2H),7.65(d,J＝8.3Hz,2H),7.39-7.31(m,2H),7.26-7.19(m,1H),4.05(s,3H),3.80(s,3H),2.37(s,3H)。m/z：401[M+H] ⁺ (esi+), rt=0.87 LCMS method 2.

Step 2:3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methylpyridazine-4-carboxylic acid: lithium hydroxide (117 mg,4.90 mmol) was added to a solution of 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-pyridazine-4-carboxylic acid methyl ester (891 mg,2.23 mmol) in anhydrous THF (19 mL) and water (2.5 mL) at room temperature and the reaction was stirred at room temperature for 16h. The reaction mixture was concentrated to low volume (THF removed), diluted in water (about 20 mL) and washed with TBME (about 20 mL). The alkaline aqueous phase is cooled to 0 ℃ and acidified to a pH of 2 to 3 by addition of 2M aqueous HCl. The organic phase was extracted with EtOAc (3X 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The crude product 3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methylpyridazine-4-carboxylic acid (91.0%) (674 mg,1.745 mmol) was obtained and used as such in the next step. Assuming a 100% molar yield.

Step 3: (R) - ((3- (3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methylpyridazine-4-carboxamide) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate:

n- [ (dimethylamino) at room temperature (3H- [1,2,3]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-N-methyl-ammonium Hexafluorophosphate (HATU) (730 mg,1.92 mmol) was added to a mixture of 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-pyridazine-4-carboxylic acid (674 mg,1.74 mmol) and N-ethyl-N-isopropyl-propan-2-amine (670 uL,3.84 mmol) in DMF (6 mL) and the reaction stirred at room temperature for 5min, followed by N- [ (R) - (3-aminophenyl) (methyl) oxo-lambda was added ⁶ -a sulfinyl group]A solution of tert-butyl carbamate (470 mg,1.74 mmol) in DMF (6 mL) and the reaction was stirred at room temperature for 16h. The reaction mixture was diluted with EtOAc (about 50 mL) and washed with water (3×about 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. By FCC (Biotage isolera, siO ₂ Gradient elution of 10-50% EtOAc in heptane) afforded (R) - ((3- (3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methylpyridazine-4-carboxamide) phenyl) (methyl) (oxo) - λ as a yellow gum ⁶ Tert-butyl (887 mg, 80%) carbamate. The material was used in the next step without further purification.

Step 4: (R) -3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) pyridazine-4-carboxamide: 4M Hydrogen chloride (4M/dioxane) (12 mL,46.8 mmol) was added to (R) - ((3- (3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methylpyridazine-4-carboxamide) phenyl) (methyl) (oxo) - λ) ⁶ In a solution of tert-butyl (598 mg,0.936 mmol) of sulfinyl) carbamate in 1, 4-dioxane (5.5 mL) and 2-propanol (5.5 mL). The mixture was stirred at room temperature for 4h. The reaction was cooled to 0deg.C and diluted in EtOAc, about 50ml. By dropwise addition of saturated NaHCO ₃ The aqueous solution was made alkaline to pH 9. The aqueous phase was extracted with EtOAc (3X 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the desired crude product which was purified by low pH reverse phase Biotage 2x (Sfar C18 12g D Duo,10%MeCN/H2O 2CV,10-25% MeCN/H) ₂ O 2CV，25-40％MeCN/H ₂ O 12CV，40％MeCN/H ₂ O8 CV then 40-100% ACN6 CV). The products containing the fractions were combined and the solvent removed in vacuo to give 381mg of the desired product as a white solid, which was diluted in ACN (30 ml) and purged with Si TMT (TCI chemical, 0.5mmol/g,1.85 g) at room temperature for 30min. The scavenger was filtered through a washpipe and concentrated to dryness in vacuo. The residue was diluted in 3:2 water: ACN (10 ml) and freeze-dried overnight to give (R) -3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide (100.0%) (331 mg, 66%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.31(s,1H),8.39(s,1H),8.02(d,J＝8.3Hz,2H),7.87(d,J＝8.6Hz,1H),7.81(d,J＝8.3Hz,2H),7.75-7.68(m,2H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.7Hz,1H),7.49(d,J＝8.2Hz,1H),4.25(s,1H),3.80(s,3H),3.07(s,3H),2.35(s,3H)。m/z：539.2[M+H] ⁺ (esi+), rt=2.67 LCMS method 6.

Example 78

Compound 1532:3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -N- {3- [ (S) -imino (meth) oxy-lambda ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide.

The title compound was synthesized in analogy to the procedure described for the preparation of example 77 compound 1531, but using 3- (4-cyano-2-methoxy-phenoxy) -6- (4-cyanophenyl) -5-methyl-pyridazine-4-carboxylic acid and N- [ (S) - (3-aminophenyl) (methyl) oxo- λ ⁶ -a sulfinyl group]Tert-butyl carbamate, which ultimately yields 3- (4-cyano-2-methoxyphenoxy) -6- (4-cyanophenyl) -N- {3- [ (S) -imino (meth) oxy-lambda ⁶ Thio group]Phenyl } -5-methylpyridaOxazine-4-carboxamide (279 mg,0.513 mmol). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.29(s,1H),8.40(s,1H),8.02(d,J＝8.2Hz,2H),7.88(d,J＝8.5Hz,1H),7.81(d,J＝8.3Hz,2H),7.75-7.68(m,2H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.7Hz,1H),7.49(d,J＝8.2Hz,1H),4.26(s,1H),3.80(s,3H),3.07(s,3H),2.35(s,3H)。0.3WT％ACN.m/z：539.0[M+H] ⁺ (esi+), rt=2.67 MET-uPLC-AB-101 (7 min, low pH).

Compounds 1533 to 1537 were prepared using the relevant route but using the appropriate commercial boric acid/ester/BF 3 salt for the Suzuki step and the appropriate chiral intermediate N- [ (S) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate or N- [ (R) - (3-aminophenyl) (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate is used as a related chiral sulfoximine product.

Compound 1533:3- (4-cyano-2-methoxyphenoxy) -6- [4- (difluoromethyl) phenyl ]-N- {3- [ (S) -imino (meth) oxo-lambda ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ ))δ11.29(s,1H),8.40(s,1H),7.88(d,J＝8.0Hz,1H),7.83-7.68(m,6H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.6Hz,1H),7.49(d,J＝8.2Hz,1H),7.14(t,J＝55.8Hz,1H),4.25(s,1H),3.81(s,3H),3.07(s,3H),2.35(s,3H)。

m/z：564.0[M+H] ⁺ (esi+), rt=2.91 LCMS method 4.

Compound 1534:3- (4-cyano-2-methoxyphenoxy) -6- [4- (difluoromethyl) phenyl]-N- {3- [ (R) -imino (meth) oxo- λ ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ ))δ11.29(s,1H),8.40(s,1H),7.88(d,J＝8.6Hz,1H),7.81-7.67(m,6H),7.62(t,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.7Hz,1H),7.49(d,J＝8.2Hz,1H),7.14(t,J＝55.8Hz,1H),4.25(s,1H),3.81(s,3H),3.07(s,3H),2.35(s,3H)。

m/z：564.0[M+H] ⁺ (esi+), rt=2.91 LCMS method 4.

Compound 1535:3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (R) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -6- (4-methoxyphenyl) -5-methylpyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),7.97(m,1H),7.83(m,1H),7.65(t,J＝8.0Hz,1H),7.54-7.46(m,3H),7.46-7.38(m,2H),7.12-7.06(m,2H),3.87(s,3H),3.83(s,3H),3.17(s,3H),2.42(s,3H)。m/z：544.1[M+H] ⁺ (esi+), rt=2.68 LCMS method 4.

Compound 1536:3- (4-cyano-2-methoxyphenoxy) -N- {3- [ (S) -imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -6- (4-methoxyphenyl) -5-methylpyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),7.97(m,1H),7.82(m,1H),7.65(t,J＝8.0Hz,1H),7.53-7.46(m,3H),7.45-7.36(m,2H),7.13-7.04(m,2H),3.87(s,3H),3.82(s,3H),3.17(s,3H),2.42(s,3H)。m/z：544.4[M+H] ⁺ (esi+), rt=2.77 LCMS method 4.

Compound 1537:3- (4-cyano-2-methoxyphenoxy) -6- (2-fluorophenyl) -N- {3- [ (R) -imino (meth) oxy- ] -lambda ⁶ Thio group]Phenyl } -5-methylpyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),7.97(m,1H),7.83(m,J＝7.8,1.8,1.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.59(m,1H),7.52(d,J＝1.7Hz,1H),7.51-7.41(m,3H),7.38(td,J＝7.5,1.1Hz,1H),7.31(m,1H),3.84(s,3H),3.17(s,3H),2.33(d,J＝1.4Hz,3H)。

m/z：532.1[M+H] ⁺ (esi+), rt=2.71 LCMS method 4.

Example 79

Compound 1538:5- [ [3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl ] amino ] thiazole-2-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ12.70(s,1H),8.05(s,1H),7.77(s,1H),7.76-7.73(m,2H),7.57(dd,J＝8.2,1.8Hz,1H),7.51(d,J＝8.2Hz,1H),3.78(s,3H),2.48(m,3H)。m/z：479.1[M+H] ⁺ (esi+), rt=2.73 MET-uPLC-AB-101 (7 min, low pH).

Compound 1539: n- (6-carbamoyl-3-pyridinyl) -3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

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¹ H NMR(500MHz,DMSO-d ₆ )δ11.47(s,1H),8.87(d,J＝2.4Hz,1H),8.32(dd,J＝8.6,2.5Hz,1H),8.10(d,J＝8.5Hz,1H),8.08-8.01(m,1H),7.75(d,J＝1.8Hz,1H),7.61(s,1H),7.57(dd,J＝8.2,1.8Hz,1H),7.53(d,J＝8.2Hz,1H),3.80(s,3H),2.54(d,J＝1.4Hz,3H)。

m/z：473.1[M+H] ⁺ (esi+), rt=2.69 MET-uPLC-AB-107 (7 min, high pH)

Compound 1540:3- (4-cyano-2-methoxy-phenoxy) -N- (5-cyano-3-pyridinyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.98(d,J＝2.5Hz,1H),8.71(d,J＝1.8Hz,1H),8.68(dd,J＝2.5,1.8Hz,1H),7.54(d,J＝1.4Hz,1H),7.45(t,J＝1.3Hz,2H),3.81(s,3H),2.59(q,J＝1.5Hz,3H)。m/z：455.0[M+H] ⁺ (esi+), rt=3.35 MET-uPLC-AB-101 (7 min, low pH)

Compound 1541: n- (3-carbamoyl-4-methoxy-phenyl) -3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.14(d,J＝2.8Hz,1H),8.01(dd,J＝9.0,2.8Hz,1H),7.53(d,J＝1.6Hz,1H),7.46-7.42(m,2H),7.22(d,J＝9.0Hz,1H),4.00(s,3H),3.81(s,3H),2.61-2.55(m,3H)。m/z：502.0[M+H] ⁺ (esi+), rt=3.00 MET-uPLC-AB-101 (7 min, low pH)

Compound 1542:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- ((methylsulfonyl) carbamoyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.12(s,1H),7.88-7.83(m,1H),7.66-7.61(m,1H),7.46-7.41(m,2H),7.38-7.32(m,2H),3.72(s,3H),3.23(s,3H),2.50(d,J＝1.4Hz,3H)。m/z：550.0[M+H] ⁺ (esi+), rt=1.97 MET-uPLC-AB-107 (7 min, high pH)

Compound 1543:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- (3-pyridyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.21(br.s,1H),8.82(d,J＝2.4Hz,1H),8.39(dd,J＝4.7,1.3Hz,1H),8.16(ddd,J＝8.3,2.6,1.5Hz,1H),7.74(d,J＝1.7Hz,1H),7.56(dd,J＝8.2,1.8Hz,1H),7.51(d,J＝8.2Hz,1H),7.45(dd,J＝8.3,4.7Hz,1H),3.79(s,3H),2.53-2.51(m,3H)。m/z：430.2[M+H] ⁺ (esi+), rt=2.99 MET-uPLC-AB-101 (7 min, low pH)

Compound 1544:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- (1-oxopyridin-1-ium-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ9.04(t,J＝1.9Hz,1H),8.21-8.15(m,1H),7.76(m,1H),7.60-7.52(m,2H),7.45(s,2H),3.81(s,3H),2.58(m,3H)。m/z：446.2[M+H] ⁺ (esi+), rt=2.44 MET-uPLC-AB-101 (7 min, low pH).

Compound 1545:3- (4-cyano-2-methoxy-phenoxy) -N- [3- [ (E) -N-methoxy-C-methyl-carbo-imidoyl ] phenyl ] -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.06(s,1H),8.03-7.98(m,1H),7.78-7.71(m,2H),7.56(dd,J＝8.2,1.8Hz,1H),7.50(d,J＝8.2Hz,1H),7.47-7.42(m,2H),3.92(s,3H),3.79(s,3H),2.52-2.51(m,3H),2.18(s,3H)。m/z：500.0[M+H] ⁺ (esi+), rt=4.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1546:3- [ [3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carbonyl ] amino ] benzoic acid methyl ester

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-63.30.m/z：487.1[M+H] ⁺ (esi+), rt=3.57 MET-uPLC-AB-107 (7 min, high pH)

Compound 1547:3- (4-fluoro-2-methyl-phenoxy) -6- (1-hydroxyethyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD) δ,8.46 (t, j=1.9 hz, 1H), 8.02-7.89 (m, 1H), 7.86-7.77 (m, 1H), 7.65 (t, j=8.0 hz, 1H), 7.16 (dd, j=8.9, 4.9hz, 1H), 7.05 (dd, j=9.1, 2.9hz, 1H), 7.01-6.93 (m, 1H), 5.23 (q, j=6.5 hz, 1H), 3.17 (s, 3H), 2.56 (s, 3H), 2.16 (s, 3H), 1.61 (d, j=6.6 hz, 3H) no 3 exchangeable H is observed. m/z:459.1[ M+H ]] ⁺ (esi+), rt=2.25 MET-uPLC-AB-107 (7 min, high pH)

Compound 1548:3- (4-cyano-2-methoxy-phenoxy) -N- (3-cyanophenyl) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.35(s,1H),8.18(d,J＝1.6Hz,1H),7.91(d,J＝8.0Hz,1H),7.76(d,J＝1.8Hz,1H),7.65(dt,J＝15.6,7.7Hz,3H),7.57(dd,J＝8.2,1.8Hz,1H),7.52(d,J＝8.2Hz,1H),3.80(s,3H)。m/z：454.2[M+H] ⁺ (esi+), rt=3.52 MET-uPLC-AB-101 (7 min, low pH).

Compound 1549: n- (3-carbamoylphenyl) -3- (3, 4-difluoro-2-methoxy-phenoxy) -5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,DMSO-d ₆ )δ11.10(s,1H),8.18(t,J＝1.8Hz,1H),8.01(br.s,1H),7.81(ddd,J＝8.1,2.2,0.9Hz,1H),7.67(dt,J＝7.8,1.0Hz,1H),7.48(t,J＝7.9Hz,1H),7.41(br.s,1H),7.33-7.26(m,1H),7.24(ddd,J＝9.3,5.2,1.9Hz,1H),3.83-3.79(m,3H),2.54-2.52(m,3H)。m/z：483.1[M+H] ⁺ (esi+), rt=3.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1550:3- [ (6-cyclopropyl-2-methoxy-3-pyridinyl) oxy ] -5-methyl-N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(500MHz,CD ₃ OD)δ8.46-8.43(m,1H),7.98-7.94(m,1H),7.85-7.81(m,1H),7.68-7.63(m,1H),7.46-7.44(m,1H),6.93-6.90(m,1H),3.81(s,3H),3.17(s,3H),2.59-2.55(m,3H),2.07-2.01(m,1H),1.04-0.99(m,2H),0.96-0.91(m,2H)。m/z：522.3[M+H] ⁺ (esi+), rt=3.48 MET-uPLC-AB-107 (7 min, high pH).

Compound 1551:3- (3, 4-difluoro-2-methoxy-phenoxy) -5-methyl-N- (tetrazolo [1,5-a ] pyridin-7-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD)δ9.09(d,J＝7.5Hz,1H),8.67(s,1H),7.48-7.39(m,1H),7.18-7.01(m,2H),3.86(s,3H),2.61(s,3H)。m/z：481.9[M+H] ⁺ (esi+), rt=3.98 MET-uPLC-AB-101 (7 min, low pH).

Compound 1552:3- (4-chloro-3-fluoro-2-methoxy-phenoxy) -5-methyl-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO)δ11.40(s,1H),8.38(d,J＝1.8Hz,1H),7.91(d,J＝7.9Hz,1H),7.79-7.66(m,2H),7.45(dd,J＝9.0,7.8Hz,1H),7.28(dd,J＝9.0,1.9Hz,1H),3.80(d,J＝1.2Hz,3H),3.25(s,3H),2.57-2.52(m,3H)。m/z：534.1,536.0[M+H] ⁺ (esi+), rt=3.65 MET-uPLC-AB-101 (7 min, low pH).

Compound 1553:3- (4-fluoro-2-methyl-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.19(s,1H),9.06(s,1H),8.38(t,J＝1.9Hz,1H),7.92-7.84(m,1H),7.74-7.68(m,1H),7.61(t,J＝7.9Hz,1H),7.28-7.16(m,2H),7.10(td,J＝8.5,3.1Hz,1H),4.23(s,1H),3.08-3.05(m,3H),2.39(s,3H),2.10(s,3H)m/z：414.9[M+H] ⁺ (esi+), rt=3.19 MET-uPLC-AB-101 (7 min, low pH).

Example 80

Compounds 1554, 1555 and 1556 are prepared by similar procedures as described for example 77 using 3- (4-cyano-2-methoxy-phenoxy) -6-iodo-5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide coupled with the appropriate boronate or boronic acid.

Compound 1554:6- (1-acetyl-3, 6-dihydro-2H-pyridin-4-yl) -3- (4-cyano-2-methoxy-phenoxy) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD) delta 8.44 (t, j=1.9 hz, 1H), 7.99-7.92 (m, 1H), 7.86-7.78 (m, 1H), 7.65 (t, j=8.0 hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.05-5.96 (m, 1H), 4.31-4.22 (m, 2H), 3.89-3.76 (m, 5H), 3.17 (s, 3H), 2.68-2.59 (m, 1H), 2.57-2.49 (m, 1H), 2.46 (s, 3H), 2.18 (2×s, amide rotamers, 3H). No 2 exchangeable H were observed. m/z:561.1[ M+H ]] ⁺ ,(ESI+) Rt=2.05 MET-uPLC-AB-107 (7 min, high pH)

Compound 1555:3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) -N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD) δ8.44 (t, j=1.9 hz, 1H), 8.00-7.90 (m, 1H), 7.85-7.77 (m, 1H), 7.65 (t, j=8.0 hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 5.95 (dt, j=2.5, 1.1hz, 1H), 3.80 (s, 3H), 3.27-3.19 (m, 2H), 3.17 (s, 3H), 2.77 (t, j=5.7 hz, 2H), 2.63-2.56 (m, 2H), 2.47 (s, 3H), 2.44 (s, 3H). No 2 exchangeable H were observed. m/z:533.1[ M+H ]] ⁺ (esi+), rt=2.20 MET-uPLC-AB-107 (7 min, high pH).

Compound 1556:3- (4-cyano-2-methoxy-phenoxy) -6- (2, 5-dihydrofuran-3-yl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

¹ H NMR(400MHz,CD ₃ OD) δ8.45 (t, j=1.9 hz, 1H), 8.01-7.92 (m, 1H), 7.86-7.79 (m, 1H), 7.65 (t, j=8.0 hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.70-6.62 (m, 1H), 5.13 (td, j=4.7, 2.1hz, 2H), 4.94 (td, j=4.7, 1.9hz, 2H), 3.80 (s, 3H), 3.17 (s, 3H), 2.60 (s, 3H) no 2 exchangeable H was observed. m/z:506.1[ M+H ] ] ⁺ (esi+), rt=2.24 MET-uPLC-AB-107 (7 min, high pH).

Example 81

Exemplary compounds of the invention are provided below. The numbering of each compound is provided directly below its structural formula.

TABLE 14

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Example 82

General synthetic pathway for the synthesis of substituted analogs

Compound 1557:

pathway 1:2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide

Reagents and conditions: a) 4-fluoro-2-methylphenol, naH, DMF; b) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, cuI, HMPA, DMF,160 ℃; c) KOH, meOH/H ₂ O,160 ℃; d) (3-aminophenyl) (methyl) (oxo) -6-sulfinyl) carbamic acid tert-butyl ester, POCl ₃ Pyridine, 0 ℃; e) TFA, DCM

Step 1: 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinic acid methyl ester: to a solution of 4-fluoro-2-methylphenol (1.08 g,8.5 mmol) in DMF (7 mL) was added sodium hydride (60%, 0.21g,8.5 mmol). The mixture was stirred at room temperature for 0.5h. The mixture was then added to a solution of methyl 5-bromo-2-chloro-4-methylpyridine-3-carboxylate (1.5 g,5.7 mmol) in DMF (8 mL). The mixture was heated at 70℃for 4h. LCMS showed the reaction was complete. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=2/1) to give methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinate (1.1 g,49.2% yield). LC-MS: (ESI) C ₁₅ H ₁₄ BrFNO ₃ Calculated value of [ M+H ]] ⁺ m/z 356.02, experimental 355.90.

Step 2:2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinic acid methyl ester: at 150℃under N ₂ To 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylpyridine-3-carboxylic acid methyl ester (500 mg,1.41 mmol), HMPA (506 mg,2.82 mmol) and copper (I) iodide (538 mg,2.82 mmol) under an atmospheremmol) to a stirred solution of NMP (10 mL) was added dropwise methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (1.36 g,7.06 mmol). The mixture was heated at 150 ℃ for 2 hours. After completion of the reaction, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 ml×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=2/1) to give methyl 2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinate (260 mg,37.6% yield). LC-MS: (ESI) C ₁₆ H ₁₄ F ₄ NO ₃ Calculated value of [ M+H ]] ⁺ m/z 344.09, experimental 344.00.

Step 3:2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinic acid: to methyl 2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinate (250 mg,0.73 mmol) in MeOH/H at RT ₂ KOH (384 mg,5.83 mmol) was added to a solution of O (1/1, 4 mL). The mixture was heated at 70℃for 4 hours. After the reaction was complete, the mixture was concentrated to remove most of the MeOH. The aqueous phase was adjusted to ph=3-4 with 1N HCl and then extracted with EtOAc (20 ml×3). The combined organic phases were washed with brine, with Na ₂ SO ₄ Dried and concentrated under reduced pressure to give 2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinic acid (210 mg,78.8% yield) as a white solid. LC-MS: (ESI) C ₁₅ H ₁₂ F ₄ NO ₃ Calculated value of [ M+H ]] ⁺ m/z 330.08, experimental 329.95.

Step 4: ((3- (2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate: 2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinic acid (240 mg,0.73 mmol) and ((3-aminophenyl) (methyl) (oxo) -lambda were reacted at 0 ℃ ⁶ Tert-butyl (thionyl) carbamate (295 mg,1.09 mmol) in pyridine (5 mL) was added drop wise POCl ₃ (200. Mu.L). The reaction solution was stirred at 0℃for 1 hour. After completion of the reaction, the resulting solution was quenched with water (30 mL) and extracted with EtOAc (30 ml×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. Through siliconThe residue was purified by column chromatography on gel (PE/etoac=2/1) to give ((3- (2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ) as a white solid ⁶ Tert-butyl sulfinyl) carbamate (70 mg,14.9% yield). LC-MS: (ESI) C ₂₇ H ₂₈ F ₄ N ₃ O ₅ Calculated value of S [ M+H ]] ⁺ m/z 582.17, experimental 582.15.

Step 5:2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide: to a solution of tert-butyl ((3- (2- (4-fluoro-2-methylphenoxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ6-sulfinyl) carbamate (70 mg,0.12 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated. The residue was dissolved in THF (2 mL) followed by saturated NaHCO ₃ The aqueous solution was adjusted to ph=8-9. The resulting solution was extracted with DCM (10 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. By preparative HPLC (Gemini 5um C ₁₈ Column, 150 x 21.2mm, with 40% to 85% MeCN/H with 0.1% fa ₂ O elution) to give 2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide (32.1 mg, 52%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ Ppm) δ11.17 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.89 (d, j=8.0 hz, 1H), 7.70 (d, j=7.8 hz, 1H), 7.61 (t, j=7.9 hz, 1H), 7.19 (dd, j=8.6, 5.2hz, 2H), 7.09 (td, j=8.5, 2.9hz, 1H), 4.24 (s, 1H), 3.07 (s, 3H), 2.48 (s, 3H), 2.08 (s, 3H). LC-MS: calculated value C of (ESI) ₂₂ H ₂₀ F ₄ N ₃ O ₃ S[M+H] ⁺ m/z 482.12, experimental 482.00.

Pathway 2:2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide

Reagents and conditions: a) K (K) ₂ CO ₃ Acetonitrile, 60 ℃; b) Difluoro (fluoro sulfonyl) methyl acetate, cuI, TBAI, DMF,70 ℃; c) Barium hydroxide, H ₂ O,90 ℃ for 70h; d) 1-bromo-3- (methylthio) benzene, pd ₂ (dba) ₃ XantPhos, 1, 4-dioxane, 100 ℃; bis (acetoxy) iodobenzene, (NH) ₄ )CO ₃ 、MeOH。

Step 1:2- (4-fluoro-2-methyl-phenoxy) -5-iodo-4-methyl-pyridine-3-carbonitrile: 4-fluoro-2-methyl-phenol (53 mg,4.22 mmol), 2-chloro-5-iodo-4-methyl-pyridine-3-carbonitrile (980 mg,3.52 mmol) and K ₂ CO ₃ A mixture of (284 mg,4.22 mmol) in acetonitrile (5 mL) was stirred at 60℃for 16h. The reaction mixture was treated again with 4-fluoro-2-methyl-phenol (533 mg,4.22 mmol) and stirred at 60 ℃ for a further 6h. The reaction was cooled to room temperature, filtered and washed with MeCN (20 mL). The filtrate was concentrated in vacuo to give a crude residue. Purification by silica chromatography (Biotage Isolera,50g Sfar Duo column) eluting with a gradient of 0 to 13% etoac/heptane afforded 2- (4-fluoro-2-methyl-phenoxy) -5-iodo-4-methyl-pyridine-3-carbonitrile (94.0%) as a white solid (930 mg,2.37mmol, 67%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(s,1H),7.25-7.18(m,2H),7.14-7.05(m,1H),2.62(s,3H),2.08(s,3H)。m/z：369.1[M+H] ⁺ (esi+), rt=1.04 LCMS method 2

Step 2:2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) pyridine-3-carbonitrile: to a mixture of 2- (4-fluoro-2-methyl-phenoxy) -5-iodo-4-methyl-pyridine-3-carbonitrile (94%, 930mg,2.37 mmol), cuprous iodide (680 mg,3.56 mmol) and tetrabutylammonium iodide (352 mg,0.950 mmol) in DMF (10 mL) was added difluoro (fluorosulfonyl) acetic acid methyl ester (2281 mg,11.9 mmol) and stirred at 70℃for 16h. The reaction was cooled to room temperature, filtered and washed with EtOAc (2×10 mL). The filtrate was washed with brine (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give a crude residue. Purification by silica chromatography (Biotage Isolera,50g Sfar Duo column) eluting with a gradient of 0 to 5% etoac/heptane afforded 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) as a yellow solid) Pyridine-3-carbonitrile (53 mg,1.39mmol,59% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.66(s,1H),7.29-7.22(m,2H),7.13(td,J＝8.5,3.2Hz,1H),2.70-2.66(m,3H),2.10(s,3H)。m/z：311.3[M+H] ⁺ (esi+), rt=1.02 LCMS method 2

Step 3:2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) pyridine-3-carboxamide: 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) pyridine-3-carbonitrile (53 mg,1.39 mmol) was suspended in water (4 mL) and barium hydroxide (1.19 g,6.96 mmol) was added. The resulting mixture was stirred at 90℃for 16h. The reaction mixture was diluted with water (4 mL) and treated again with barium hydroxide (1.19 g,6.96 mmol). Stirring was resumed for a total of 70h at 90 ℃. The cooled reaction mixture was diluted with water (50 mL) and acidified to pH 1 using 5M HCl. The aqueous solution was extracted with EtOAc (3X 15 mL) and the combined organics were dried over MgSO ₄ Dried and concentrated under reduced pressure. The crude product was purified by FCC (Biotage Isolera 4, 10g Sfar Duo, lambda-all collected) using a gradient of 0-50-100% EtOAc/heptane followed by 0-20% meoh/EtOAc. The product fractions were combined and concentrated under reduced pressure to give 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) as a white powder (220 mg, 47%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.39(s,1H),8.16(br.s,1H),7.90(br.s,1H),7.21-7.04(m,3H),2.42(s,3H),2.07(s,3H)。m/z：329.1[M+H] ⁺ (esi+), rt=0.81 LCMS method 2.

Step 4:2- (4-fluoro-2-methyl-phenoxy) -4-methyl-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: to a degassed solution of 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-5- (trifluoromethyl) pyridine-3-carboxamide (98%, 200mg,0.597 mmol), 1-bromo-3- (methylthio) benzene (97 ul,0.719 mmol) and cesium carbonate (284 mg,1.79 mmol) in anhydrous 1, 4-dioxane (3 mL) was added (1 e,4 e) -1, 5-diphenylpentan-1, 4-dien-3-one-palladium (3:2) Pd ₂ (dba) ₃ (27 mg,0.0295 mmol) and (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine [ XantPhos)](35 mg,0.0605 mmol). The reaction was degassed for an additional 5 minutes, then the vial was sealed and stirred at 100 ℃ for 4 hours. The cooled reaction mixture was diluted with EtOAc (5 mL) and passed through celite And (5) filtering by using a soil pad. The celite was washed with EtOAc (2×3 mL) and the combined filtrates were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was dried using a phase separation cartridge and concentrated under vacuum to give 352mg of yellow solid. The crude product was purified by column chromatography (Sfar Duo 10g, eluting with 0-100% etoac/heptane, λ -all collected) the product eluates were combined and concentrated under reduced pressure to give the desired product, 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (72.0%) (240 mg, 0.284 mmol, 64%) as a pale yellow powder. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.83(s,1H),8.50(s,1H),7.70(t,J＝1.9Hz,1H),7.47-7.43(m,1H),7.31(t,J＝8.0Hz,1H),7.21-7.16(m,2H),7.09(td,J＝8.5,2.9Hz,1H),7.04(ddd,J＝7.9,1.8,0.9Hz,1H),2.48-2.44(m,6H),2.08(s,3H)。m/z：451.1[M+H] ⁺ (esi+), rt=1.09 LCMS method 2.

Step 5:2- (4-fluoro-2-methyl-phenoxy) -4-methyl-N- [3- (methylsulfonyl) phenyl]-5- (trifluoromethyl) pyridine-3-carboxamide: to a solution of 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (72%, 240mg,0.384 mmol) in methanol (7.5 mL) was added bis (acetoxy) iodobenzene (399mg, 1.23 mmol) and ammonium carbonate (75 mg,0.797 mmol) and the reaction was stirred at room temperature for 15h. The reaction mixture was treated again with bis (acetoxy) iodobenzene (132 mg,0.410 mmol) and ammonium carbonate (25 mg,0.266 mmol) and stirred for 2h, then allowed to stand at ambient temperature over the weekend. Stirring was resumed for 1h prior to treatment. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography using 0-100% EtOAc/heptane followed by 0-20% meoh/EtOAc (on a Biotage Sfar Duo 10g column, lambda-all collected). The resulting residue was dried in a vacuum oven at 40℃for 2 hours to give 2- (4-fluoro-2-methyl-phenoxy) -4-methyl-N- [3- (methylsulfonyl) phenyl ] as an off-white powder ]-5- (trifluoromethyl) pyridine-3-carboxamide (95.0%) (98 mg,0.193mmol, 50%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.17(s,1H),8.51(s,1H),8.44-8.37(m,1H),7.92-7.84(m,1H),7.72-7.67(m,1H),7.61(t,J＝7.9Hz,1H),7.22-7.15(m,2H),7.09(td,J＝8.5,3.0Hz,1H),4.23(s,1H),3.07(s,3H),2.49-2.47(m,3H),2.08(s,3H)。m/z：482.2[M+H] ⁺ (esi+), rt=3.12 LCMS method 4.

Example 83

Compound 1558: 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) nicotinamide

Reagents and conditions: a) NCS, DCM,0 ℃; b) Phopcl ₂ 170 ℃; c) 4-fluoro-2-methylphenol, naH, DMF,70 ℃; d) KOH, meOH/H ₂ O,60 ℃; e) ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -sulfoalkyl) carbamic acid tert-butyl ester, SOCl ₂ 50 ℃; followed by DIPEA, DCM,0 ℃; f) TFA, DCM

Step 1: 5-chloro-2-hydroxy-4-methylnicotinic acid methyl ester: to a solution of methyl 4-methyl-2-oxo-1, 2-dihydropyridine-3-carboxylate (5.0 g,30 mmol) in DCM (50 mL) at 0deg.C was added NCS (4.0 g,30 mmol). The mixture was stirred at the same temperature for 60 minutes. The mixture was quenched with water (50 mL) and extracted with DCM (50 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by wet milling with (PE/etoac=3/1) to give methyl 5-chloro-2-hydroxy-4-methylnicotinate (4 g,66% yield) as a pale brown solid. LC-MS: (ESI) C ₈ H ₉ ClNO ₃ Calculated value of [ M+H ]] ⁺ m/z 202.02, experimental 202.0.

Step 2:2, 5-dichloro-4-methylnicotinic acid methyl ester: a solution of methyl 5-chloro-2-hydroxy-4-methylnicotinate (2.0 g,10 mmol) in phenyl dichlorophosphate (10 mL) was heated to 170℃for 2 hours. The resulting solution was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=10/1) to give methyl 2, 5-dichloro-4-methylnicotinate (1 g,45% yield) as a pale yellow oil. LC-MS: (ESI) C ₈ H ₈ Cl ₂ NO ₂ Calculated value of [ M+H ]] ⁺ m/z 219.99, experimental 220.0.

Step 3: 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinic acid methyl ester: to a solution of 4-fluoro-2-methylphenol (284 mg,2.27 mmol) in DMF (5 mL) was added NaH (60%, 110mg,2.72 mmol) at 0deg.C. The mixture was stirred at the same temperature for 60 minutes, followed by addition of methyl 2, 5-dichloro-4-methylnicotinate (500 mg,2.27 mmol). The mixture was heated at 70℃for 16 hours. The resulting mixture was quenched with water (20 mL) and extracted with DCM (50 mL. Times.2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/etoac=3/1) to give methyl 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinate (250 mg,35% yield) as a pale yellow oil. ¹ H NMR(400MHz,CDCl ₃ ,ppm)δ8.05(s,1H),7.06-6.76(m,3H),3.98(s,3H),2.39(s,3H),2.13(s,3H)。

Step 4: 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinic acid: to a solution of methyl 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinate (250 mg,0.81 mmol) in MeOH (5 mL) was added a solution of KOH (457 mg,8.1 mmol) in water (2 mL). The solution was heated at 60℃for 16 hours. The resulting mixture was adjusted to ph=3-4 with 1N HCl and extracted with EtOAc (30 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinic acid (150 mg,63% yield) as a white solid. LC-MS: (ESI) C ₁₄ H ₁₂ ClFNO ₃ Calculated value of [ M+H ]] ⁺ m/z 296.04, experimental 296.0.

Step 5: (3- (5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinamide) phenyl) (methyl) (oxo) - λ6-sulfinyl) carbamic acid tert-butyl ester: 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinic acid (100 mg,0.34 mmol) in SOCl ₂ The solution in (1 mL) was heated to 50deg.C and stirred for 0.5 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Followed by reaction at 0deg.C to ((3-aminophenyl) (methyl) (oxo) - λ) ⁶ In a stirred solution of tert-butyl (92 mg,0.34 mmol) and DIPEA (88 mg,0.68 mmol) in DCM (2 mL) Chloride intermediate was added. The resulting mixture was stirred at 25℃for 1h. The mixture was then quenched with water (10 mL) and extracted with DCM (10 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=1/1) to give ((3- (5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinamide) phenyl) (methyl) (oxo) - λ) as a white oil ⁶ Tert-butyl sulfinyl) carbamate (80 mg,43% yield). LC-MS: (ESI) C ₂₆ H ₂₈ ClFN ₃ O ₅ Calculated value of S [ M+H ]] ⁺ m/z 548.13, experimental 548.0.

Step 6: preparation of 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) nicotinamide: to a solution of tert-butyl ((3- (5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methylnicotinamide) phenyl) (methyl) (oxo) -sulfanylidene) carbamate (80 mg,0.14 mmol) in DCM (5 mL) was added TFA (1 mL) at 0 ℃. The mixture was stirred at 25℃for 1 hour. The resulting mixture was saturated with NaHCO ₃ The aqueous solution was adjusted to ph=8-9 and extracted with DCM (10 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC (Gemini 5um C ₁₈ Column, 150 x 21.2mm, with 30% to 90% MeCN/H with 0.1% fa ₂ O elution) to give 5-chloro-2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) nicotinamide (25 mg, 38%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ,ppm)δ11.09(s,1H),8.41(s,1H),8.22(s,1H),7.88(d,J＝8.1Hz,1H),7.69(d,J＝7.9Hz,1H),7.60(t,J＝7.9Hz,1H),7.16(dd,J＝8.8,4.6Hz,2H),7.10-7.03(m,1H),4.23(s,1H),3.06(s,3H),2.39(s,3H),2.08(s,3H)。LC-MS：(ESI)C ₂₁ H ₂₀ ClFN ₃ O ₃ Calculated value of S [ M+H ]] ⁺ m/z 448.08, experimental 448.05.

Example 84

Compound 1559: (R) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide

Reagents and conditions: a) H ₂ O ₂ 、NaOH、THF/H ₂ O; b) 5-bromo-2-chloro-4-methylnicotinic acid methyl ester, naH, DMF,70 ℃; c) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, cuI, HMPA, DMF,160 ℃; d) KOH, meOH/H ₂ O,70 ℃; e) (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -sulfoalkyl) carbamic acid tert-butyl ester, SOCl ₂ 、DIPEA、DCM；f)TFA、DCM

Step 1: 6-fluoro-2-methylpyridin-3-ol: to a solution of (6-fluoro-2-methylpyridin-3-yl) boronic acid (2.5 g,16.12 mmol) in THF (20 mL) at 0deg.C was added NaOH (516 mg,12.89 mmol), H ₂ O (5 mL) and H ₂ O ₂ (1 mL, 30%). The mixture was stirred at room temperature for 1h. The mixture was then adjusted to ph=3-4 with 1N HCl and extracted with EtOAc (20 ml×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=3/1) to give 6-fluoro-2-methylpyridin-3-ol (1.8 g,70.59% yield) as a yellow solid. L-CMS: (ESI) C ₆ H ₆ Calculated value of FNO [ M+H ]] ⁺ m/z 128.05, experimental 128.15.

Step 2: 5-bromo-2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methylnicotinic acid methyl ester: to a solution of 6-fluoro-2-methylpyridin-3-ol (1.50 g,11.81 mmol) in DMF (8 mL) was added sodium hydride (60%, 977mg,23.62 mmol) at 0deg.C. The mixture was stirred at room temperature for 0.5h. To a stirred solution of methyl 5-bromo-2-chloro-4-methylnicotinate (2.08 g,7.91 mmol) in DMF (8 mL) was then added the mixture. The mixture was heated at 70℃for 4h. LCMS showed the reaction was complete. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=2/1) to give methyl 5-bromo-2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methylnicotinate (0.71 g,16.9% yield). LC-MS: (ESI) C ₁₄ H ₁₃ BrFN ₂ O ₃ Calculated value of (2)[M+H] ⁺ m/z 355.01, experimental 354.95.

Step 3:2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinic acid methyl ester: at 150℃under N ₂ To a stirred solution of methyl 5-bromo-2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methylnicotinate (650 mg,1.84 mmol), HMPA (618 mg,3.68 mmol) and copper (I) iodide (703 mg,3.68 mmol) in NMP (10 mL) was added dropwise methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (3.53 g,18.4 mmol) under an atmosphere. The mixture was heated at 150 ℃ for 2 hours. After completion of the reaction, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 ml×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=2/1) to give methyl 2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinate (330 mg,51.9% yield). LC-MS: (ESI) C ₁₅ H ₁₃ F ₄ N ₂ O ₃ Calculated value of [ M+H ]] ⁺ m/z345.09, experimental 345.05.

Step 4:2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinic acid: to 2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinic acid methyl ester (300 mg,0.87 mmol) in THF/H at room temperature ₂ KOH (487 mg,8.69 mmol) was added to a solution of O (1/1, 4 mL). The mixture was heated at 70℃for 4 hours. After the reaction was completed, the mixture was concentrated to remove most of THF. The aqueous phase was adjusted to ph=3-4 with 1N HCl and then extracted with EtOAc (20 ml×3). The combined organic phases were washed with brine, with Na ₂ SO ₄ Dried and concentrated under reduced pressure to give 2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinic acid (280 mg, 97.2%) as a white solid. LC-MS: (ESI) C ₁₄ H ₁₁ F ₄ N ₂ O ₃ Calculated value of [ M+H ]] ⁺ m/z 331.07, experimental 331.00.

Step 5: (R) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate: 2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl5- (trifluoromethyl) nicotinic acid (120 mg,0.36 mmol) in SOCl ₂ The solution in (1 mL) was heated to 50deg.C and stirred for 0.5h. The solution was concentrated under vacuum to provide the chloride intermediate. Followed by directing the reaction mixture at 0℃toward (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ To a stirred solution of tert-butyl sulfinyl) carbamate (117 mg,0.43 mmol) and DIEA (88 mg,0.68 mmol) in DCM (2 mL) was added the chloride intermediate. The resulting mixture was stirred at 25℃for 1h. The mixture was then quenched with water (10 mL) and extracted with DCM (10 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=1/1) to give tert-butyl (R) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ6-sulfinyl) carbamate (100 mg, 47.6%) as a white oil. LC-MS: (ESI) C ₂₆ H ₂₇ F ₄ N ₄ O ₅ Calculated value of S [ M+H ]] ⁺ m/z 583.17, experimental 583.10.

Step 6: (R) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide: to a solution of tert-butyl (R) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ6-sulfinyl) carbamate (100 mg,0.17 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated. The residue was dissolved in THF (2 mL) followed by saturated NaHCO ₃ The aqueous solution was adjusted to ph=8-9. The resulting solution was extracted with DCM (10 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. By preparative HPLC (Gemini 5um C ₁₈ Column, 150 x 21.2mm, containing 0.05% nh with 40% to 95% ₄ MeCN/H of OH ₂ O elution) to give (R) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide (57.2 mg, 69.6%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ,ppm)δ11.20(s,1H),8.55(s,1H),8.41(s,1H),7.96-7.78(m,2H),7.74-7.56(m,2H),7.11(dd,J＝8.7,3.4Hz,1H),4.24(s,1H),3.32(s,3H),3.07(s,3H),2.25(s,3H)。LC-MS：(ESI)C ₂₁ H ₁₉ F ₄ N ₄ O ₃ Calculated value of S [ M+H ]] ⁺ m/z 483.11, experimental 483.00.

Example 85

Compound 1560: (S) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide

Reagents and conditions: a) (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -sulfoalkyl) carbamic acid tert-butyl ester, SOCl ₂ 、DIPEA、DCM；b)TFA、DCM

Step 1: (S) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate: 22- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinic acid (120 mg,0.36 mmol) was reacted in SOCl ₂ The solution in (1 mL) was heated to 50deg.C and stirred for 0.5h. The solution was then concentrated under vacuum to provide the chloride intermediate. Followed by reaction at 0deg.C to (S) - ((3-aminophenyl) (methyl) (oxo) - λ ⁶ To a stirred solution of tert-butyl sulfinyl) carbamate (117 mg,0.43 mmol) and DIEA (88 mg,0.68 mmol) in DCM (2 mL) was added the chloride intermediate. The resulting mixture was stirred at 25℃for 1h. The mixture was then quenched with water (10 mL) and extracted with DCM (10 ml×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/etoac=1/1) to give (S) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ as a white oil ⁶ Tert-butyl sulfinyl) carbamate (100 mg,47.6% yield). LC-MS: (ESI) C ₂₆ H ₂₇ F ₄ N ₄ O ₅ Calculated value of S [ M+H ]] ⁺ m/z 583.17, experimental value 583.15。

Step 2: (S) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide: (S) - ((3- (2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda @ at room temperature ⁶ To a solution of tert-butyl (alkylene) carbamate (100 mg,0.17 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated. The residue was dissolved in THF (2 mL) followed by saturated NaHCO ₃ The aqueous solution was adjusted to ph=8-9. The resulting solution was extracted with DCM (10 mL. Times.3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. By preparative HPLC (Gemini 5um C ₁₈ Column, 150 x 21.2mm, containing 0.05% nh with 40% to 95% ₄ MeCN/H of OH ₂ O elution) to give (S) -2- ((6-fluoro-2-methylpyridin-3-yl) oxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide (61.3 mg,74.6% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ Ppm) δ11.20 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.99-7.76 (m, 2H), 7.76-7.52 (m, 2H), 7.11 (dd, j=8.6, 3.4hz, 1H), 4.24 (s, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 2.25 (s, 3H). LC-MS: calculated value C of (ESI) ₂₁ H ₁₉ F ₄ N ₄ O ₃ S[M+H] ⁺ m/z 483.11, experimental 482.95.

Example 86

Exemplary compounds of the present invention are provided below

Compound 1561: general approach 1:2- (4-cyano-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) K (K) ₂ CO ₃ ACN,70 ℃; b) LiOH, THF, water, room temperature; c) EDC, 3-aminobenzenesulfonamide and pyridine

Step 1:2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid methyl ester: a mixture of methyl 2-chloro-5-trifluoromethyl-nicotinic acid (100 mg,0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg,0.624 mmol) and potassium carbonate (87 mg,0.629 mmol) in dry acetonitrile (2.5 mL) was stirred in a reduced pressure vial at 70℃for 18 hours. The reaction mixture was cooled to room temperature, diluted with MeCN, filtered through a phase separator, and the solid was washed with MeCN (2 times). The combined filtrates were concentrated under reduced pressure to give a crude material. This crude compound was purified by FCC (Biotage Isolera 4 flash purification system, sfar Duo 10g,0-40% etoac/heptane) to give the desired product as a white powder, methyl 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylate (94.0%) (142 mg,0.379mmol, 91%). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 8.73-8.70 (m, 1H), 8.60-8.58 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.50 (m, 1H), 7.44-7.41 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H). LC-MS method 2.m/z 353.1[ M+H ]] ⁺ ,(ESI+),RT＝0.96。

Step 2.2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid: to a mixture of methyl 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylate (142 mg,0.403 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (35 mg,0.834 mmol) and the mixture was stirred at room temperature for 3h. The reaction mixture was diluted with water and adjusted to pH 2 by the dropwise addition of 2M HCl. Extracted with EtOAc (3 times), over MgSO ₄ Dried and concentrated in vacuo to give the desired product, 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (94.0%) (127 mg,0.353mmol,88% yield) as a white powder. The product was used in the next step crude product.

Step 3.2- (4-cyano-2-methoxy-phenoxy) -N- (3-sulfamoylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: to 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (94%, 63mg,0.175 mmol) and N- [3- (dimethylamino) propyl]To a solution of N' -ethylcarbodiimide hydrochloride (1:1) (67 mg,0.350 mmol) in pyridine (1.2 mL) was added 3-aminobenzenesulfonamide (60 mg,0.348 mmol). The mixture was stirred at room temperature for 2h. Removing solvent The agent (co-evaporated with MeCN) and the residue purified by preparative HPLC (prep method 3). The fractions containing the desired product were combined and evaporated to white powder which was freeze dried overnight to give the desired product as an off-white powder, 2- (4-cyano-2-methoxy-phenoxy) -N- (3-sulfamoylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) (53 mg,0.105mmol,60% yield). ¹ H NMR (500 MHz, DMSO-d 6) delta 10.91 (s, 1H), 8.68-8.64 (m, 1H), 8.57-8.54 (m, 1H), 8.32-8.29 (m, 1H), 7.87-7.83 (m, 1H), 7.70-7.68 (m, 1H), 7.61-7.49 (m, 4H), 7.44-7.38 (m, 2H), 3.76 (s, 3H). LC-MS method 4: m/z 493.1[ M+H ]] ⁺ ,(ESI+),RT＝3.24。

Compound 1562:2- (4-cyano-2-methoxyphenoxy) -N- {3- [ imino (methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) HATU, DIPEA, DMF, 3- (methylthio) aniline; b) (NH) ₄ ) ₂ CO ₃ 、PIDA、MeOH

Step 1:2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: to a mixture of 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (71 mg,0.210 mmol), DIPEA (0.11 mL,0.630 mmol) and HATU (96 mg,0.252 mmol) in DMF (1.2 mL) was added 3- (methylthio) aniline (31 ul,0.252 mmol). The reaction was stirred at room temperature for 4h. The reaction mixture was then poured into water and extracted with EtOAc (2 times). The combined organic phases were washed with brine solution (2 times) over MgSO ₄ Dried, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by FCC (Biotage Isolera 4, 10g Sfar Duo, lambda-all collected) using a 0-50% etoac/heptane gradient to give 2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (80.0%) as a brown oil (68 mg,0.118mmol,56% yield). ¹ H NMR(500MHz,DMSO-d6)δ10.62(s,1H),8.66-8.64(m,1H),8.54-8.51 (m, 1H), 7.72-7.66 (m, 2H), 7.57-7.49 (m, 2H), 7.48-7.43 (m, 1H), 7.31 (t, j=8.0 hz, 1H), 7.05-7.01 (m, 1H), 3.76 (s, 3H), 2.48-2.47 (m, 3H). LC-MS method 2: m/z 460.1[ M+H ]] ⁺ ,(ESI+),RT＝1.06。

Step 2:2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]-5- (trifluoromethyl) pyridine-3-carboxamide: to a solution of 2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (96%, 68mg,0.142 mmol) in methanol (0.8 mL) was added diammonium carbonate (20 mg,0.213 mmol) and bis (acetoxy) (phenyl) -lambda-3-iodoalkane (PIDA) (107 mg,0.332 mmol) at room temperature and the reaction was stirred at room temperature for 17h. The reaction mixture was concentrated to dryness in vacuo to give the crude product, which was subsequently purified using FCC (0-100%EtOAc,Sfar Duo 10g, dry-loaded onto silica with DCM). The fractions 9-12 were combined, evaporated and lyophilized overnight to give the desired product, 2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl, as an off-white powder ]-5- (trifluoromethyl) pyridine-3-carboxamide (99.0%) (49 mg,0.0989mmol,70% yield). ¹ H NMR (500 MHz, DMSO-d 6) delta 10.94 (s, 1H), 8.68-8.65 (m, 1H), 8.56 (d, 1H), 8.39-8.35 (m, 1H), 7.97-7.92 (m, 1H), 7.72-7.67 (m, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.56-7.48 (m, 2H), 4.23 (s, 1H), 3.76 (s, 3H), 3.06 (s, 3H). LC-MS method 4: m/z 491.1[ M+H ]] ⁺ ,(ESI+),RT＝2.94。

Compound 1563:general approach 2:2- [4- (difluoromethoxy) phenoxy]-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) 50% propylphosphonic anhydride, DIPEA, DMAP, 3- (methylsulfonyl) aniline; b) 4- (difluoromethoxy) phenol, K ₂ CO ₃ 、ACN，60℃

Step 1.2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: 2-chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (2.00 g,8.87 mmol), 50% propylphosphonic acidA mixture of anhydride solution/EtOAc (50%, 6.3mL,10.6 mmol), N-ethyl-N-isopropyl-propan-2-amine (3.1 mL,17.7 mmol) and N, N-dimethylpyridine-4-amine (0.22 g,1.77 mmol) was dissolved in DCM (44.336 mL) at room temperature under nitrogen. After 10 minutes 3- (methylsulfonyl) aniline (1.82 g,10.6 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 4h. IPC showed the desired product. The reaction mixture was poured into water (20 mL) and brine (10 mL) and extracted with DCM (3×50 mL), dried over sodium sulfate and concentrated. Purification by silica chromatography eluting with a gradient of 0 to 38% etoac/heptane afforded 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (99.0%) as a yellow solid (1.90 g,4.97mmol,56% yield). ¹ H NMR (500 mhz, dmso-d 6) δ11.15 (s, 1H), 9.05-9.00 (m, 1H), 8.70 (d, j=2.3 hz, 1H), 8.34 (t, j=1.8 hz, 1H), 7.97-7.92 (m, 1H), 7.76-7.66 (m, 2H), 3.24 (s, 3H). LC-MS method 1:m/z 378.95[ M+H ]] ⁺ ,(ESI+),RT＝1.09。

Step 2:2- [4- (difluoromethoxy) phenoxy]-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: a mixture of 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (99%, 100mg,0.261 mmol), 4- (difluoromethoxy) phenol (63 mg, 0.399mmol) and dipotassium carbonate (54 mg, 0.399mmol) in acetonitrile (0.5411 mL) was stirred at 60℃for 1h. IPC1 showed the desired product. The reaction was cooled to room temperature, filtered and washed with MeCN (15 mL). The filtrate was concentrated in vacuo to give a crude residue. Purification by silica chromatography eluting with a gradient of 0 to 70% EtOAc in heptane afforded 2- [4- (difluoromethoxy) phenoxy ] as an off-white solid]-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (99.0%) (102 mg,0.200mmol,77% yield). ¹ H NMR (500 mhz, dmso-d 6) δ11.02 (s, 1H), 8.71-8.66 (m, 1H), 8.55 (d, j=2.3 hz, 1H), 8.38 (t, j=1.8 hz, 1H), 7.97 (dt, j=7.6, 1.7hz, 1H), 7.73-7.63 (m, 2H), 7.41-7.08 (m, 5H), 3.22 (s, 3H). LC-MS method 5:m/z 502.9[ M+H ] ] ⁺ ,(ESI+),RT＝4.44。

Compound 1564:general approach 3:n- [3- (methylsulfonyl) phenyl group]-5- (trifluoromethyl) -2- [4- (trifluoromethyl) phenoxy ]]Pyridine-3-carboxamides

Reagents and conditions: a) 50% propylphosphonic anhydride, DIPEA, DMAP, 3- (methylsulfonyl) aniline; b) (NH) ₄ ) ₂ CO ₃ PIDA, meOH; c) 4- (trifluoromethyl) phenol, K ₂ CO ₃ ，60℃

Step 1: 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide: a mixture of 2-chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (4.00 g,17.7 mmol) was dissolved in DCM (80 mL) at room temperature and treated with 50% propylphosphonic anhydride solution/EtOAc (50%, 13mL,21.3 mmol) and N-ethyl-N-isopropyl-propan-2-amine (6.2 mL,35.5 mmol). Followed by stirring at room temperature for 30 minutes. N, N-lutidine-4-amine (0.43 g,3.55 mmol) and 3- (methylthio) aniline (2.2 mL,17.7 mmol) were then added together in one portion. The reaction mixture was stirred at room temperature for 2h. The mixture was poured into water (60 mL) and brine (60 mL) and extracted with DCM (3×40 mL), dried (MgSO ₄ ) And concentrated. Purification by column chromatography (50 g,0 to 10% ea/heptane) afforded 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (6.12 g,17.6mmol,100% yield) as a yellow solid. ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) delta 10.79 (s, 1H), 9.04-8.98 (m, 1H), 8.66 (d, j=2.1 hz, 1H), 7.66 (s, 1H), 7.34 (t, j=7.9 hz, 1H), 7.06 (d, j=8.3 hz, 1H), 2.49 (s, 3H). LC-MS method 1:m/z 347.1[ M+H ]] ⁺ ,(ESI+),RT＝0.93。

Step 2: 2-chloro-N- [3- (methylsulfonyl) phenyl ]]-5- (trifluoromethyl) pyridine-3-carboxamide: [ acetoxy (phenyl) - λ3-iodo]Acetate (348 mg,1.08 mmol) was dissolved in methanol (7.2096 mL) and treated with 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (250 mg,0.721 mmol) and diammonium carbonate (104 mg,1.08 mmol), each added in one portion. The reaction was stirred at room temperature for 18h. The mixture was concentrated in vacuo to give a crude residue. Elution by silica chromatography with a gradient of 0 to 30% EtOAc/heptanePurification gave 2-chloro-N- [3- (methylsulfonyl) phenyl ] as a beige solid]-5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) (171 mg,0.444mmol,62% yield). ¹ H NMR (500 mhz, dmso-d 6) δ11.08 (s, 1H), 9.02 (dd, j=2.4, 0.8hz, 1H), 8.74-8.63 (m, 1H), 8.32 (t, j=1.9 hz, 1H), 7.92 (ddd, j=8.0, 2.1,1.0hz, 1H), 7.71 (ddd, j=7.8, 1.7,1.1hz, 1H), 7.63 (t, j=7.9 hz, 1H), 4.25 (s, 1H), 3.07 (d, j=0.9 hz, 3H). LC-MS method 1:m/z 378.95[ M+H ] ] ⁺ ,(ESI+),RT＝1.00。

Step 3: n- [3- (methylsulfonyl) phenyl group]-5- (trifluoromethyl) -2- [4- (trifluoromethyl) phenoxy ]]Pyridine-3-carboxamide: 4- (trifluoromethyl) phenol (63 mg,0.389 mmol), 2-chloro-N- [3- (methylsulfonyl) phenyl ]]A suspension of 5- (trifluoromethyl) pyridine-3-carboxamide (98%, 150mg,0.389 mmol) and dipotassium carbonate (81 mg, 0.284 mmol) in acetonitrile (0.8055 mL) was heated to 60℃under nitrogen for 2h. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The filtrate was purified by preparative HPLC (preparation 1) to give N- [3- (methylsulfonyl) phenyl ] as a white solid]-5- (trifluoromethyl) -2- [4- (trifluoromethyl) phenoxy ]]Pyridine-3-carboxamide (97.0%) (97 mg,0.187mmol,48% yield). ¹ H NMR (500 mhz, dmso-d 6) δ11.01 (s, 1H), 8.75-8.68 (m, 1H), 8.61-8.56 (m, 1H), 8.37 (t, j=1.8 hz, 1H), 7.99-7.94 (m, 1H), 7.89-7.81 (m, 2H), 7.75-7.66 (m, 1H), 7.61 (t, j=7.9 hz, 1H), 7.53 (d, j=8.5 hz, 2H), 4.24 (s, 1H), 3.06 (s, 3H). LC-MS method 5:m/z 503.9[ M+H ]] ⁺ ,(ESI+),RT＝4.20。

Compound 1565:general approach 4:n- (3-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl-3-pyridinyl]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) 3-aminobenzamide, EDC, pyridine; b) 6- (Cyclobutoxy) -2-methyl-pyridin-3-ol, K ₂ CO ₃ 、ACN、65℃

Step 1: n- (3-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-methylAmide: to a solution of 2-chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (4.00 g,17.7 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (4.08 g,21.3 mmol) in pyridine (60 mL) was added 3-aminobenzamide (2.66 g,19.5 mmol). The mixture was stirred at room temperature for one hour and then concentrated in vacuo. The residue was taken up on SiO2 and purified by column chromatography (SiO 2,0 to 100% ea/heptane) to give N- (3-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-carboxamide (99%) (EV-TXY 001-053-001) (4.51 g,13.1mmol,74% yield) as an off-white solid. LC-MS ¹ H NMR analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) δ10.87 (s, 1H), 9.01 (d, j=1.6 hz, 1H), 8.67 (d, j=2.4 hz, 1H), 8.16 (t, j=1.8 hz, 1H), 8.00 (s, 1H), 7.85 (dd, j=8.0, 1.3hz, 1H), 7.66 (d, j=7.9 hz, 1H), 7.47 (t, j=7.9 hz, 1H), 7.40 (s, 1H). LC-MS method 2: m/z 344.1[ M+H ]] ⁺ ,(ESI+),RT＝0.65。

Step 2: n- (3-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl-3-pyridinyl]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide: to a mixture of N- (3-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-carboxamide (50 mg,0.145 mmol) and 6- (cyclobutoxy) -2-methyl-pyridin-3-ol (34 mg,0.189 mmol) in anhydrous acetonitrile (0.5 mL) was added dipotassium carbonate (30 mg,0.218 mmol). The mixture was heated in a pressure flask at 65 ℃ for 2 hours. The mixture was filtered and concentrated to give a pale yellow oil. Purification by preparative HPLC (prep method 2). The fractions containing the product were combined to give N- (3-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl-3-pyridinyl ] as a white solid ]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide (99%) (57 mg,0.117mmol,81% yield). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(500MHz,CD ₃ OD) δ8.55 (s, 2H), 8.19 (s, 1H), 7.96 (m, 1H), 7.69 (d, j=7.8 hz, 1H), 7.55 (d, j=8.7 hz, 1H), 7.51 (t, j=7.9 hz, 1H), 6.66 (d, j=8.8 hz, 1H), 5.13 (m, 1H), 2.54-2.45 (m, 2H), 2.27 (s, 3H), 2.21-2.09 (m, 2H), 1.93-1.82 (m, 1H), 1.80-1.67 (m, 1H). LC-MS method 4: m/z 487.2[ M+H ]] ⁺ (esi+), rt=3.70 LC-MS method 4.

Compound 1566:universal usePathway 5:n- (4-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl-3-pyridinyl]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) 4-aminobenzamide, EDC, pyridine; b) 6- (Cyclobutoxy) -2-methyl-pyridin-3-ol, K ₂ CO ₃ 、ACN，65℃

Step 1: n- (4-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-carboxamide: to a solution of 2-chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (4.00 g,17.7 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (4.08 g,21.3 mmol) in pyridine (60 mL) was added 4-aminobenzamide (2.66 g,19.5 mmol). The mixture was stirred at room temperature for one hour and then concentrated in vacuo. The residue was taken up on SiO2 and purified by column chromatography (SiO ₂ Purification of 0 to 100% ea/heptane) afforded (100%) N- (4-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-carboxamide (3.33 g,9.67mmol,55% yield) as an off-white solid. ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(500MHz,CD ₃ OD) delta 8.76 (d, j=1.7 hz, 2H), 8.32 (d, j=2.3 hz, 1H), 7.85-7.79 (m, 2H), 7.73-7.67 (m, 2H), 7.57-7.50 (m, 1H), 6.59-6.52 (m, 1H). LC-MS method 2: m/z 344.0[ M+H ]] ⁺ ,(ESI+),RT＝0.65。

Step 2: n- (4-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl-3-pyridinyl]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide: to a mixture of N- (4-carbamoylphenyl) -2-chloro-5- (trifluoromethyl) pyridine-3-carboxamide (50 mg,0.145 mmol) and 6- (cyclobutoxy) -2-methyl-pyridin-3-ol (34 mg,0.189 mmol) in anhydrous acetonitrile (0.5 mL) was added dipotassium carbonate (30 mg,0.218 mmol). The mixture was heated in a pressure flask at 65 ℃ for 2 hours. The mixture was filtered and concentrated to give an orange oil. Purification by preparative HPLC (prep method 2). The fractions containing the product were combined to give (100%) N- (4-carbamoylphenyl) -2- [ [6- (cyclobutoxy) -2-methyl ] as a white solidPhenyl-3-pyridinyl]Oxy group]-5- (trifluoromethyl) pyridine-3-carboxamide (49 mg,0.101mmol, 69%). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(500MHz,CD ₃ OD) delta 8.58-8.51 (m, 2H), 7.94 (d, j=8.8 hz, 2H), 7.85 (d, j=8.7 hz, 2H), 7.55 (d, j=8.7 hz, 1H), 6.66 (d, j=8.8 hz, 1H), 5.13 (p, j=7.1 hz, 1H), 2.54-2.44 (m, 2H), 2.27 (s, 3H), 2.21-2.09 (m, 2H), 1.93-1.82 (m, 1H), 1.80-1.67 (m, 1H). LC-MS method 4: m/z 487.2[ M+H ]] ⁺ ,(ESI+),RT＝3.68。

Compound 1567:general approach 6:5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]Pyridine-3-carboxamides

Reagents and conditions: a) 3, 4-difluoro-2-methoxy-phenol, cs ₂ CO ₃ DMF,80 ℃; b) LiOH, water, THF; c) 3- (methylthio) aniline, EDC, pyridine; d) (NH) ₄ ) ₂ CO ₃ 、PIDA、MeOH

Step 1: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester: to a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g,3.99 mmol) and 3, 4-difluoro-2-methoxy-phenol (0.83 g,5.19 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (1.95 g,5.99 mmol). The mixture was heated in a pressure flask at 80 ℃ for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4×15 mL) and brine (15 mL). The organics were dried (MgSO 4), filtered and concentrated to give an orange oil. Purification by FCC (25 g 20 μm,0 to 15% ea/heptane) afforded 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester (95.0%) (EV-TXY 001-100-002) (1.15 g,2.92mmol,73% yield) as a white solid. LC-MS ¹ H NMR analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.29 (d, j=2.5 hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z374.1[ M+H ]] ⁺ ,(ESI+),RT＝1.00。

Step (a)2: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid: to a solution of methyl 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (1.15 g,3.07 mmol) in THF (8 mL): water (2 mL) was added lithium hydroxide (0.17 g,6.76 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 10 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (97.0%) as a white solid (1.04 g,2.79mmol, 91%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(500MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.27 (d, j=2.6 hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 360.1[ M]+,(ESI+),RT＝0.86。

Step 3: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide: to a solution of 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (300 mg,0.833 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (192 mg,1.00 mmol) in anhydrous pyridine (3 mL) was added 3- (methylthio) aniline (139 mg,1.00 mmol). The mixture was stirred at room temperature for 0.5h. LC-MS analysis indicated completion of the reaction. The solvent was removed in vacuo and the residue was purified by FCC (10 g,0 to 30% ea/heptane) to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (92.0%) as a clear oil (402 mg,0.768mmol,92% yield). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(400MHz,CD ₃ OD) δ8.38 (d, j=2.5 hz, 1H), 8.28 (d, j=2.5 hz, 1H), 7.72 (t, j=2.0 hz, 1H), 7.39 (m, 1H), 7.28 (t, j=8.0 hz, 1H), 7.17-7.00 (m, 3H), 3.84 (d, j=1.7 hz, 3H), 2.49 (s, 3H). LC-MS method 2: m/z 481.1[ M]+,(ESI+),RT＝1.12。

Step 4: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]Pyridine-3-carboxamide: to 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (400 mg,0.831 mmol) in methanol at room temperatureTo a solution in (12 mL) was added phenylammonium diacetate (PIDA) (803 mg,2.49 mmol) and diammonium carbonate (235 mg,2.49 mmol) and the reaction was stirred at room temperature for 1 hr. The solvent was removed in vacuo and the residue was purified by FCC (10 g,0 to 100% ea/heptane) to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl as a white solid]Pyridine-3-carboxamide (88.0%) (328 mg,0.563mmol,68% yield). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. 30mg was purified by preparative HPLC (preparative method 2). The product fractions were combined, concentrated under reduced pressure and the resulting residue was freeze-dried from MeCN-water (1:1) to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] as a white solid ]Pyridine-3-carboxamide (100.0%) (17 mg,0.0332mmol, 4.0%). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(400MHz,CD ₃ OD) δ8.44 (t, j=2.0 hz, 1H), 8.40 (d, j=2.5 hz, 1H), 8.31 (d, j=2.5 hz, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 7.63 (t, j=8.0 hz, 1H), 7.17-7.00 (m, 2H), 3.84 (d, j=1.7 hz, 3H), 3.17 (s, 3H). LC-MS method 7:m/z 512.2[ M]+,(ESI+),RT＝3.33。

Compound 1568:general approach 7:5-bromo-N- (3-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide

Reagents and conditions: a) Cs (cells) ₂ CO ₃ DMF,80 ℃; b) LiOH, water, THF; c) 3-aminobenzamide, EDC and pyridine

Step 1: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester: to a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g,3.99 mmol) and 3, 4-difluoro-2-methoxy-phenol (0.83 g,5.19 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (1.95 g,5.99 mmol). The mixture was heated in a pressure flask at 80 ℃ for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4×15 mL) and brine (15 mL). The organics were dried (MgSO ₄ ) Filtering and concentrating to obtainOrange oil. Purification by FCC (25 g 20 μm,0 to 15% ea/heptane) afforded 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester (95.0%) as a white solid (1.15 g,2.92mmol, 73%). LC-MS ¹ H NMR analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.29 (d, j=2.5 hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 374.1[ M+H ]] ⁺ ,(ESI+),RT＝1.00。

Step 2: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid: to a solution of methyl 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (1.15 g,3.07 mmol) in THF (8 mL): water (2 mL) was added lithium hydroxide (0.17 g,6.76 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 10 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (97.0%) as a white solid (1.04 g,2.79mmol, 91%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(500MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.27 (d, j=2.6 hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 360.1[ M] ⁺ ,(ESI+),RT＝0.86。

Step 3: 5-bromo-N- (3-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide: to a solution of 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (300 mg,0.833 mmol) and 3- (ethyliminomethylamino) -N, N-dimethyl-propan-1-amine hydrochloride (192 mg,1.00 mmol) in anhydrous pyridine (3 mL) was added 3-aminobenzamide (139 mg,1.00 mmol). The mixture was stirred at room temperature for 0.5 hours. The solvent was removed and the residue was purified by FCC (10 g,0 to 100% ea/heptane) to give 5-bromo-N- (3-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (92.0%) as a white solid (385 mg,0.741mmol, 89%). ¹ H NMR and LC-MS analysis indicated this was the desired product. Further purification by preparative HPLC (prep. method 2) was 30mg.The product fractions were combined, concentrated under reduced pressure and the resulting residue was freeze-dried from MeCN-water (1:1) to give 5-bromo-N- (3-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (100.0%) as a white solid (23 mg,0.0481mmol, 5.8%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.42 (d, j=2.5 hz, 1H), 8.30 (d, j=2.5 hz, 1H), 8.16 (t, j=2.0 hz, 1H), 7.92 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, j=7.9 hz, 1H), 7.13 (m, 1H), 7.10-7.02 (m, 1H), 3.84 (d, j=1.7 hz, 3H). LC-MS method 4: m/z 478.1[ M]+,(ESI+),RT＝3.36。

Compound 1569:general approach 8:5-bromo-N- (4-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide

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Reagents and conditions: a) Cs (cells) ₂ CO ₃ DMF,80 ℃; b) LiOH, water, THF; c) 4-aminobenzamide, EDC and pyridine

Step 1: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester: to a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g,3.99 mmol) and 3, 4-difluoro-2-methoxy-phenol (0.83 g,5.19 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (1.95 g,5.99 mmol). The mixture was heated in a pressure flask at 80 ℃ for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4×15 mL) and brine (15 mL). The organics were dried (MgSO ₄ ) Filtered and concentrated to give an orange oil. Purification by FCC (25 g 20 μm,0 to 15% ea/heptane) afforded 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid methyl ester (95.0%) as a white solid (1.15 g,2.92mmol,73% yield). LC-MS ¹ H NMR analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.29 (d, j=2.5 hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 374.1[ M+H ]] ⁺ ,(ESI+),RT＝1.00。

Step 2:5-Bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid: to a solution of methyl 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (1.15 g,3.07 mmol) in THF (8 mL): water (2 mL) was added lithium hydroxide (0.17 g,6.76 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 10 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (97.0%) as a white solid (1.04 g,2.79mmol, 91%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(500MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.27 (d, j=2.6 hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 360.1[ M ]+,(ESI+),RT＝0.86。

Step 3: 5-bromo-N- (4-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide: to a solution of 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (300 mg,0.833 mmol) and 3- (ethyliminomethylamino) -N, N-dimethyl-propan-1-amine hydrochloride (192 mg,1.00 mmol) in anhydrous pyridine (3 mL) was added 4-aminobenzamide (139 mg,1.00 mmol). The mixture was stirred at room temperature for 0.5h. LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by FCC (10 g,0 to 100% EA/heptane followed by 0 to 5% meoh/EA) to give 5-bromo-N- (4-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (95.0%) as a white solid (298 mg, 0.292 mmol, 71%). 1H-19F-NMR and LC-MS analysis indicated this was the desired product. Purification by preparative HPLC (prep. method 2) of 30mg, after freeze drying, yielded 5-bromo-N- (4-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (100.0%) as a white solid (21 mg,0.0439mmol, 5.3%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.39 (d, j=2.5 hz, 1H), 8.30 (d, j=2.5 hz, 1H), 7.95-7.87 (m, 2H), 7.85-7.78 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 3.84 (d, j=1.7 hz, 3H). LC-MS method 3: m/z 478.2[ M ]+,(ESI+),RT＝3.36

Compound 1570:general approach 9:5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N-pyridazin-4-yl-pyridine-3-carboxamide

Reagents and conditions: a) Cs (cells) ₂ CO ₃ DMF,80 ℃; b) LiOH, water, THF; c) Pyridazin-4-amines, EDC, pyridine

Step 2: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid: to a solution of methyl 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (1.15 g,3.07 mmol) in THF (8 mL): water (2 mL) was added lithium hydroxide (0.17 g,6.76 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 10 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (97.0%) as a white solid (1.04 g,2.79mmol, 91%). ¹ H NMR and LC-MS analysis indicated that this was the desired product。 ¹ H NMR(500MHz,CD ₃ OD) δ8.44 (d, j=2.6 hz, 1H), 8.27 (d, j=2.6 hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, j=1.4 hz, 3H). LC-MS method 2: m/z 360.1[ M]+,(ESI+),RT＝0.86。

Step 3: 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N-pyridazin-4-yl-pyridine-3-carboxamide: to a solution of 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (165 mg,0.458 mmol) and 3- (ethyliminomethylamino) -N, N-dimethyl-propan-1-amine hydrochloride (105 mg,0.550 mmol) in anhydrous pyridine (1.65 mL) was added pyridazin-4-amine (52 mg,0.550 mmol). The mixture was stirred at room temperature for 1h. LC-MS analysis (EV-TXY 001-107-IPC 1) indicated the reaction was complete. The solvent was removed and the residue was purified by FCC (10 g,0 to 100% ea in heptane) to give 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N-pyridazin-4-yl-pyridine-3-carboxamide (146 mg, 0.336 mmol,73% yield) as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(400MHz,CD ₃ OD) δ9.41 (dd, j=2.7, 1.0hz, 1H), 9.07 (dd, j=6.0, 1.0hz, 1H), 8.43 (d, j=2.5 hz, 1H), 8.34 (d, j=2.5 hz, 1H), 8.23 (dd, j=6.0, 2.7hz, 1H), 7.16-7.00 (m, 2H), 3.83 (d, j=1.7 hz, 3H). LC-MS method 3: m/z 437.1[ M ] ⁺ ,(ESI+),RT＝3.24。

Compound 1571:general approach 10:3- [ [2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carbonyl]Amino group]Bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester

Reagents and conditions: a) 3-Aminobicyclo [1.1.1]Pentane-1-carboxylic acid ester hydrochloride, EDC, pyridine; b) Difluoro-2-methoxy-phenol, K ₂ CO ₃ 、ACN，65℃

Step 1:3- [ 2-chloro-5- (trifluoromethyl) pyridine-3-carbonyl]Bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester: to a solution of 2-chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (100 mg, 0.447 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (102 mg, 0.284 mmol) in pyridine (1.5 mL) was addedAdding 3-amino-bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester hydrochloride (79 mg, 0.447 mmol). The mixture was stirred at room temperature for 1h. LC-MS analysis indicated that the reaction was largely complete. The solvent was removed and the residue was purified by FCC (10 g,0 to 40% ea in heptane) to give 3- [ [ 2-chloro-5- (trifluoromethyl) pyridine-3-carbonyl ] as a white solid]Amino group]Bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester (100%) (126 mg,0.361mmol, 82%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.82 (d, j=1.6 hz, 1H), 8.25 (d, j=2.3 hz, 1H), 3.72 (s, 3H), 2.46 (s, 6H). LC-MS method 2: m/z 349.0[ M+H ] ] ⁺ ,(ESI+),RT＝0.76。

Step 2:3- [ [2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carbonyl]Amino group]Bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester: to 3- [ [ 2-chloro-5- (trifluoromethyl) pyridine-3-carbonyl]Amino group]Bicyclo [1.1.1]To a mixture of pentane-1-carboxylic acid methyl ester (50 mg,0.143 mmol) and 3, 4-difluoro-2-methoxy-phenol (30 mg,0.186 mmol) in anhydrous acetonitrile (0.5 mL) was added dipotassium carbonate (30 mg,0.215 mmol). The mixture was heated in a pressure flask at 65 ℃ for 3 hours. LC-MS analysis indicated completion of the reaction. The mixture was filtered and concentrated to give a clear oil. Purification by FCC (10 g,0 to 20% EA/heptane) afforded 3- [ [2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carbonyl ] as a white solid]Amino group]Bicyclo [1.1.1]Pentane-1-carboxylic acid methyl ester (99.0%) (55 mg,0.115mmol,80% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.51 (dd, j=2.4, 0.9hz, 1H), 8.44 (d, j=2.4 hz, 1H), 7.14-7.03 (m, 2H), 3.85 (d, j=1.8 hz, 3H), 3.71 (s, 3H), 2.47 (s, 6H). LC-MS method 6: m/z 473.3[ M+H ]] ⁺ ,(ESI+),RT＝3.98。

Compound 1572:general approach 11:2- (4-cyano-2-methoxy-phenoxy) -N- (1-oxopyridin-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ ACN,80 ℃; b) LiOH, water, THF; c) Pyridin-3-amine, EDC, pyridine; d) MCPBA, DCM

Step 1:2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid methyl ester: a mixture of methyl 2-chloro-5-trifluoromethyl-nicotinic acid (100 mg,0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg,0.624 mmol) and potassium carbonate (87 mg,0.629 mmol) in dry acetonitrile (2.5 mL) was stirred in a reduced pressure vial at 80℃for 1 hour. LC-MS analysis indicated that the reaction was largely complete. The mixture was filtered and concentrated to give a clear oil. Purification by FCC (5 g,0 to 40% ea/heptane) afforded methyl 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylate (100.0%) as a white semi-solid (142 mg,0.403mmol, 97%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) δ8.73 (m, 1H), 8.60 (d, j=2.5 hz, 1H), 7.69 (d, j=1.8 hz, 1H), 7.53 (dd, j=8.2, 1.8hz, 1H), 7.43 (d, j=8.2 hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LC-MS method 2: m/z 353.1[ M+H ]] ⁺ ,(ESI+),RT＝0.94。

Step 2:2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid: to a solution of methyl 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylate (142 mg,0.403 mmol) in THF (1.8 mL): water (0.4 mL) was added lithium hydroxide (10 mg,0.403 mmol), and the mixture was stirred at room temperature for 1h. LC-MS analysis indicated completion of the reaction. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 5 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (100.0%) as a white solid (134 mg,0.396mmol,98% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) δ8.68 (m, 1H), 8.55 (d, j=2.5 hz, 1H), 7.69 (d, j=1.8 hz, 1H), 7.53 (dd, j=8.2, 1.8hz, 1H), 7.42 (d, j=8.2 hz, 1H), 3.75 (s, 3H). LC-MS method 2: m/z 339.1[ M+H ]] ⁺ ,(ESI+),RT＝0.79。

Step 3:2- (4-cyano-2-methoxy-phenoxy) -N- (3-picolinePyridyl) -5- (trifluoromethyl) pyridine-3-carboxamide: to a solution of 2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (70 mg,0.207 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (48 mg,0.248 mmol) in pyridine (0.8 mL) was added pyridin-3-amine (21 mg,0.228 mmol). The mixture was stirred at room temperature for 1h. LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by FCC (5 g,0 to 70% ea/heptane) to give 2- (4-cyano-2-methoxy-phenoxy) -N- (3-pyridinyl) -5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) as a white solid (75 mg,0.177mmol,86% yield). 1H-19F-NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) delta 10.83 (s, 1H), 8.86 (d, j=2.5 hz, 1H), 8.67 (m, 1H), 8.58 (d, j=2.5 hz, 1H), 8.35 (dd, j=4.7, 1.5hz, 1H), 8.17 (dt, j=8.5, 1.8hz, 1H), 7.69 (m, 1H), 7.58-7.48 (m, 2H), 7.43 (dd, j=8.3, 4.7hz, 1H), 3.76 (s, 3H). LC-MS method 2: m/z 415.2[ M+H ]] ⁺ ,(ESI+),RT＝0.78。

Step 4:2- (4-cyano-2-methoxy-phenoxy) -N- (1-oxopyridin-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide: a solution of 2- (4-cyano-2-methoxy-phenoxy) -N- (3-pyridinyl) -5- (trifluoromethyl) pyridine-3-carboxamide (75 mg,0.181 mmol) in DCM (3 mL) was treated with 3-chloroperoxybenzoic acid (73%, 45mg,0.190 mmol) at 0deg.C, then allowed to warm to room temperature and stirred for 0.5h. LC-MS analysis indicated that the reaction was largely complete. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (prep. method 2) to give a white solid (about 80mg, containing mCBA). Further purification (preparation method 1) afforded 2- (4-cyano-2-methoxy-phenoxy) -N- (1-oxopyridin-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (100.0%) as a white solid (13 mg,0.0302mmol,17% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ9.10 (m, 1H), 8.58 (m, 1H), 8.54 (m, 1H), 8.19-8.13 (m, 1H), 7.81 (m, 1H), 7.58-7.41 (m, 4H), 3.80 (s, 3H). LC-MS method 4: m/z 431.2[ M+H ]] ⁺ ,(ESI+),RT＝2.63。

Example 87

Exemplary compounds of the invention are listed in table 15, prepared using one of the general routes described above.

TABLE 15

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Example 88

Compound 1716: n- [3- (N-acetyl-S-methyl-sulfinyl) phenyl ] -2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide

To (R) -2- (4-fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonyl) phenyl at room temperature]To a solution of 5- (trifluoromethyl) pyridine-3-carboxamide (50 mg,0.107 mmol) in DCM (1.0697 mL) was added pyridine (0.017 mL,0.214 mmol) and acetic anhydride (0.012 mL,0.128 mmol).The mixture was stirred at room temperature under nitrogen overnight. The reaction was concentrated under a nitrogen stream. Loaded onto a 10g Sfar Duo cartridge in DCM (3X 0.5 mL) and then eluted with 0-50% EtOAc in heptane. Concentrating the relevant eluate to obtain N- [3- (N-acetyl-S-methyl-sulfinyl) phenyl group]-2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) (45 mg,0.0873mmol, 82%). ¹ H NMR (400 MHz, DMSO-d 6) δ11.05 (s, 1H), 8.67-8.63 (m, 1H), 8.57-8.53 (m, 1H), 8.41-8.36 (m, 1H), 8.00-7.94 (m, 1H), 7.70-7.63 (m, 2H), 7.28-7.22 (m, 1H), 7.22-7.15 (m, 1H), 7.13-7.05 (m, 1H), 3.40 (s, 3H), 2.08 (s, 3H), 1.96 (s, 3H). LC-MS method 4: m/z 510.1[ M+H ] ] ⁺ ,(ESI+),RT＝3.51。

Example 89

Compound 1717: n- [3- (N, S-Dimethylsulfonyl) phenyl ] -2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide

(R) -2- (4-fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonyl) phenyl]5- (trifluoromethyl) pyridine-3-carboxamide (50 mg,0.107 mmol), copper diacetate (2+) (29 mg,0.160 mmol) and methylboronic acid (13 mg,0.214 mmol) were suspended in anhydrous 1, 4-dioxane (0.8557 mL) and stirred at room temperature under atmospheric air for 5 min. Pyridine (0.017 mL,0.214 mmol) was then added and the vessel sealed and heated to 100deg.C for 40 minutes. The reaction mixture was diluted with water (about 1.5 mL) and DCM (3 mL), vigorously shaken, and the mixture was subsequently filtered through a PTFE phase separator. The aqueous solution was re-extracted with DCM (2 mL) and the layers separated. The combined organics were concentrated under a gentle stream of nitrogen. The crude material was purified by preparative HPLC (preparation 2) to give N- [3- (N, S-dimethyl-sulfinyl) phenyl ] as a white powder]-2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (43 mg, 51%). ¹ H NMR(500MHz,DMSO-d6)δ10.97(s,1H),8.66(dd,J＝2.5,1.1Hz,1H),8.57-8.53(m,1H),8.30(t,J＝1.9Hz,1H),7.95(ddd,J＝8.0,2.2,1.2Hz,1H),7.65(t,J＝7.9Hz,1H),7.60-7.56(m,1H),7.26(dd,J＝8.9,5.1Hz,1H),7.20(ddJ=9.7, 3.2hz, 1H), 7.11 (td, j=8.5, 3.2hz, 1H), 3.11 (s, 3H), 2.49 (s, 3H), 2.09 (s, 3H). LC-MS method 6: m/z 482.3[ M+H ]] ⁺ ,(ESI+),RT＝3.62。

Example 90

Compound 1718:2- (3- (methylsulfonyl) phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide

2- (3-Methylsulfanylphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (48 mg,0.0997 mmol) was dissolved in methanol (1.0 mL) and the resulting mixture was treated with potassium bisulfate (33 mg,0.219 mmol) and stirred at room temperature. Potassium bisulfate (40 mg,0.267 mmol) was added after more than 24 hours and the reaction was stirred at room temperature for an additional 24 hours. Dilute reaction with DCM (25 mL) and NaHCO3 (saturated aqueous solution, 25 mL). Stirred vigorously for 5 minutes and filtered through a phase separator. The aqueous solution was extracted again with DCM (×1) and filtered. The combined organics were concentrated in vacuo to a white solid. Column chromatography in 0 to 100% etoac/heptane on a 10g Sfar Duo cartridge afforded 2- (3- (methylsulfonyl) phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (98.0%) (33 mg,0.0629mmol, 63%). ¹ H NMR (400 mhz, dmso-d 6) δ11.04 (s, 1H), 8.74-8.71 (m, 1H), 8.59 (d, j=2.1 hz, 1H), 8.41-8.38 (m, 1H), 7.97 (dt, j=7.3, 1.8hz, 1H), 7.91-7.84 (m, 2H), 7.76 (t, j=7.9 hz, 1H), 7.73-7.64 (m, 3H), 3.27 (s, 3H), 3.22 (s, 3H). LC-MS method 4: m/z 515.1[ M+H ] ] ⁺ ,(ESI+),RT＝3.06。

Example 91

Compound 1719: (R) - (2- (((3- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda) ⁶ -sulfoalkyl) amino) -2-oxoethyl (methyl) carbamic acid tert-butyl ester

To N- (tert-butoxycarbonyl) -N-methylglycine (18 mg,0.0941 mmol) and N- (tert-butoxycarbonyl) -N-methylglycine (18 mg,0.0941 mmol) were added DCM (0.4279 mL) at room temperature followed by N-ethyl-N- (propan-2-yl) propan-2-amine (0.036 mL,0.205 mmol). The suspension was stirred at room temperature for 5-10 minutes, followed by the addition of (R) -2- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -5- (trifluoromethyl) nicotinamide (100%, 40mg,0.0856 mmol) in one portion. The resulting suspension was stirred at room temperature. The reaction was concentrated under a nitrogen stream. Loaded onto a 10g Sfar Duo cartridge in DCM (3X 0.5 mL) and then eluted with 0-50% EtOAc in heptane. The relevant fractions were concentrated to give a colourless glass (54 mg, 99%). ¹ H NMR (400 mhz, dmso-d 6) δ11.07 (s, 1H), 8.68-8.64 (m, 1H), 8.57-8.51 (m, 1H), 8.50-8.43 (m, 1H), 8.01-7.92 (m, 1H), 7.71-7.63 (m, 2H), 7.26 (dd, j=8.9, 5.0hz, 1H), 7.20 (dd, j=9.3, 3.1hz, 1H), 7.11 (td, j=8.5, 3.1hz, 1H), 3.97-3.77 (m, 2H), 3.47 (s, 3H), 2.80-2.72 (m, 3H), 2.09 (s, 3H), 1.36 (s, 4H), 1.28 (s, 5H). LC-MS method 6: m/z 639.3[ M+H ] ] ⁺ ,(ESI+),RT＝4.15。

Example 92

Compound 1720: (R) -2- (4-fluoro-2-methylphenoxy) -N- (3- (S-methyl-N- (methylglycyl) sulphonimidoyl) phenyl) -5- (trifluoromethyl) nicotinamide

To (R) - (2- (((3- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda) at room temperature ⁶ To a solution of tert-butyl (meth) carbamate (61 mg,0.0955 mmol) in DCM (1.0 mL) was added phosphoric acid (85% wt)/water (85%, 0.044mL,0.382 mmol) (12. Mu.L). The mixture was stirred vigorously at room temperature for 2-3 hours. The reaction mixture was diluted with NaOH (2 n,5 mL) and extracted twice with DCM (2×5 mL). Each extract was filtered through a phase separator cartridge and concentrated to a brown gum. The crude material was loaded onto a 10g Sfar Duo cartridge and sequentially washed with 0-100% EtOAc in heptane and 0-50% MeOH in EtOAcElution gave (R) -2- (4-fluoro-2-methylphenoxy) -N- (3- (S-methyl-N- (methylglycyl) sulphonimidoyl) phenyl) -5- (trifluoromethyl) nicotinamide (93.5%) as a pale brown powder (36 mg,0.0625mmol,65% yield). ¹ H NMR (400 mhz, dmso-d 6) δ11.07 (s, 1H), 8.70-8.65 (m, 1H), 8.58-8.54 (m, 1H), 8.47-8.41 (m, 1H), 8.02-7.96 (m, 1H), 7.74-7.65 (m, 2H), 7.27 (dd, j=8.9, 5.0hz, 1H), 7.21 (dd, j=9.3, 3.1hz, 1H), 7.12 (td, j=8.5, 3.3hz, 1H), 3.46 (s, 3H), 3.20 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H). LC-MS method 6: m/z 539.2[ M+H ] ] ⁺ ,(ESI+),RT＝3.42。

Example 93

Compound 1721: n- (3-carbamoyl-1-bicyclo [1.1.1] pentyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide

3- [ [2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carbonyl]Amino group]Bicyclo [1.1.1]Methyl pentane-1-carboxylate (34 mg,0.0737 mmol) was dissolved in IPA (0.257 mL) and diluted with 14.5M ammonium hydroxide (1.0 mL,14.5 mmol). The solution was stirred in a pressure flask at 40℃for 2h. LC-MS analysis indicated that the reaction was largely complete. The solvent was removed and the residue was purified by preparative HPLC (prep. method 2) to give N- (3-carbamoyl-1-bicyclo [ 1.1.1) as a white solid]Pentyl) -2- (4-cyano-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (100.0%) (13 mg,0.0291mmol,40% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) δ8.47 (s, 2H), 7.54 (d, j=1.3 hz, 1H), 7.51-7.41 (m, 2H), 3.81 (s, 3H), 2.45 (s, 6H). LC-MS method 6: m/z 447.3[ M+H ]] ⁺ ,(ESI+),RT＝2.96。

Example 94

Compound 1722: n- (3-carbamoyl-1-bicyclo [1.1.1] pentyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide

3- [ [2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carbonyl ]Amino group]Bicyclo [1.1.1]Methyl pentane-1-carboxylate (35 mg,0.0741 mmol) was dissolved in IPA (0.2584 mL) and diluted with 14.5M ammonium hydroxide (0.50 mL,7.3 mmol). The solution was stirred in a pressure flask at 40℃for 1h. LC-MS analysis indicated that the reaction was largely complete. Purification by preparative HPLC (preparative method 2) gave N- (3-carbamoyl-1-bicyclo [ 1.1.1) as a white solid]Amyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (100.0%) (16 mg,0.0350mmol,47% yield). ¹ H NMR and LC-MS analysis indicated that this was the desired compound. ¹ H NMR(400MHz,CD ₃ OD) delta 8.51 (m, 1H), 8.44 (m, 1H), 7.19-7.03 (m, 2H), 3.85 (d, j=1.8 hz, 3H), 2.45 (s, 6H). LC-MS method 6: m/z 458.2[ M+H ]] ⁺ ,(ESI+),RT＝3.23。

Example 95

Compound 1723: 5-cyano-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3 (methylsulfonyl) phenyl ] pyridine-3-carboxamide

Palladium acetate (8.8 mg,0.0390 mmol) was added to (LTGO 0001070) 5-bromo-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]Pyridine-3-carboxamide (200 mg,0.390 mmol), potassium ferrocyanide hydrate (4:1:3) (82 mg,0.195 mmol), sodium carbonate (41 mg,0.390 mmol) and [2- (2-diphenylphosphinophenoxy) phenyl ]]Diphenylphosphine (42 mg,0.0781 mmol) in DMF (2 mL) and water (2 mL). The reaction mixture was heated at 70℃for 3h. LC-MS analysis indicated completion of the reaction. Dilute with water (10 mL) and extract with ethyl acetate (3 x 8 mL). The organics were dried (MgSO 4), filtered and concentrated to give an orange oil. Purification by preparative HPLC (preparative method 2) gave 5-cyano-2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] as a white solid ]Pyridine-3-carboxamide (100.0%)59mg,0.129mmol,33% yield). ¹ H and ¹⁹ f NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) delta 8.60 (d, j=2.3 hz, 1H), 8.58 (d, j=2.3 hz, 1H), 8.45 (t, j=2.0 hz, 1H), 8.03-7.95 (m, 1H), 7.81 (m, 1H), 7.64 (t, j=8.0 hz, 1H), 7.17-7.10 (m, 1H), 7.10-7.03 (m, 1H), 3.85 (d, j=1.8 hz, 3H), 3.17 (s, 3H). LC-MS method 7:m/z 459.2[ M+H ]] ⁺ ,(ESI+),RT＝2.87。

Example 96

Compound 1724: n- (3-carbamoylphenyl) -5-cyano-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide

Palladium acetate (4.7 mg,0.0209 mmol) was added to 5-bromo-N- (3-carbamoylphenyl) -2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (100 mg,0.209 mmol), potassium ferrocyanide hydrate (4:1:3) (44 mg,0.105 mmol), sodium carbonate (22 mg,0.209 mmol) and [2- (2-diphenylphosphinophenoxy) phenyl ]]Diphenylphosphine (23 mg,0.0418 mmol) in DMF (1.5 mL) and water (1.5 mL). The reaction mixture was heated at 75℃for 4h. LC-MS analysis indicated that starting material remained, but the reaction spectrum became more chaotic, so the reaction stopped. Dilute with water (10 mL) and extract with ethyl acetate (3 x 8 mL). The organics were dried (MgSO ₄ ) Filtered and concentrated to give an orange oil. Purification by preparative HPLC (prep. method 2) gave 15mg of a white solid. LC-MS analysis indicated that this was the desired compound, but not clean (84% at 215 nm). Further purification by preparative HPLC (prep. method 1) gave 10.2mg of white solid. LC-MS analysis indicated only 82% at 215 nm. Further purification by preparative HPLC (Waters Sunfire C18 column (19 mm. Times.100 mm,5 μm; temperature: room temperature), injection volume 1500. Mu.L, flow rate 20mL/min, 1.9 min at 5% B (A=0.1% formic acid/water; B=0.1% formic acid/acetonitrile, followed by a gradient of 35-95% B for 16min, followed by 2 min. UV spectra were recorded at 215nm using a Gilson detector) afforded N- (3) as a white solid Carbamoyl phenyl) -5-cyano-2- (3, 4-difluoro-2-methoxy-phenoxy) pyridine-3-carboxamide (100.0%) (6.8 mg,0.016mmol,7.7% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CDCl ₃ ) δ9.62 (s, 1H), 8.92 (d, j=2.3 hz, 1H), 8.51 (d, j=2.3 hz, 1H), 8.08 (t, j=1.9 hz, 1H), 8.02-7.96 (m, 1H), 7.60 (m, 1H), 7.49 (t, j=7.9 hz, 1H), 7.10-6.94 (m, 2H), 6.14 (s, 1H), 5.58 (s, 1H), 3.93 (d, j=2.8 hz, 3H). LC-MS method 4: m/z 425.5[ M+H ]] ⁺ ,(ESI+),RT＝2.93。

Example 97

Compound 1725:2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] -5- (3-oxabicyclo [4.1.0] hept-6-yl) pyridine-3-carboxamide

5-bromo-2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]Pyridine-3-carboxamide (40 mg,0.0798 mmol), trifluoro (3-oxabicyclo [ 4.1.0)]Potassium hept-6-yl) borate (20 mg,0.0957 mmol), cyclopentyl (diphenyl) phosphine; palladium dichloride; a mixture of iron (5.9 mg, 7.98. Mu. Mol) and cesium carbonate (52 mg,0.160 mmol) was suspended in toluene (0.8 mL) and water (0.2 mL) and subsequently degassed for 5 minutes. The mixture was heated to 80 ℃ for 2h. LC-MS analysis indicated that the starting material was exhausted. The mixture was diluted with ethyl acetate (5 mL), filtered and concentrated to a brown oil. Purification by preparative HPLC (standard method) gave 2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] as an off-white solid ]-5- (3-oxabicyclo [ 4.1.0)]Hept-6-yl) pyridine-3-carboxamide (100.0%) (20 mg,0.0386mmol,48% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CD ₃ OD) delta 8.39 (m, 1H), 8.23 (d, j=2.5 hz, 1H), 8.14 (d, j=2.5 hz, 1H), 8.01 (m, 1H), 7.83-7.76 (m, 1H), 7.63 (t, j=8.0 hz, 1H), 7.53-7.39 (m, 3H), 4.10 (dd, j=11.4, 4.5hz, 1H), 3.92 (m, 1H), 3.81 (s, 3H), 3.58 (m, 1H), 3.54-3.41 (m, 1H), 3.17 (s, 3H), 2.18 (m, 1H), 2.01 (m, 1H), 1.42 (m, 1H), 1.12 (m, 1H), 1.00 (t, j=5.4, 1H). LC-MS method 4:m/z519.2[M+H] ⁺ ,(ESI+),RT＝2.69。

example 98

Compound 1726:2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

Reagents and conditions: a) 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3, 6-dihydro-2H-pyran, pd (OAc) ₂ Dicyclohexyl- [2- (2, 4, 6-triisopropylphenyl) phenyl]Phosphine, na ₃ PO ₄ Dioxane, 80 ℃; b) PIDA, (NH) ₄ ) ₂ CO ₃ 、MeOH

Step 1:2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide: 5-bromo-2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (50 mg,0.106 mmol), dicyclohexyl- [2- (2, 4, 6-triisopropylphenyl) phenyl ]A mixture of phosphine (5.1 mg,0.0106 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyran (25 mg,0.117 mmol) and tripotassium phosphate (68 mg,0.319 mmol) in 1, 4-dioxane (0.8 mL) and water (0.2 mL) was degassed with nitrogen for 5 min, followed by palladium diacetate (2+) (2.4 mg,0.0106 mmol). The mixture was heated to 80 ℃ in a pressure flask for 8h. LC-MS analysis indicated completion of the reaction. Dilute with ethyl acetate (8 mL) and wash with water (5 mL) and brine (5 mL). The organics were dried (MgSO ₄ ) Filtration and concentration gave a brown oil. Purification by FCC (5 g,0 to 30% ea/heptane) afforded 34mg (34 mg,0.0266mmol,25% yield) of 2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide as an off-white solid. LC-MS analysis indicated this to be a mixture of about 5:4 hydrodehalogenation byproducts (1.06 min) and the desired product (1.11 min). Can be used in oxidation without further purification. LC-MS method 2: m/z 474.2[ M+H ]] ⁺ ,(ESI+),RT＝1.11。

Step 2:2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- [3- (methylsulfonyl) phenyl]Pyridine-3-carboxamide: to a solution of 2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (40%, 36mg,0.0304 mmol) in methanol (0.4 mL) was added phenyliodiammonium diacetate (PIDA) (29 mg,0.0912 mmol) and diammonium carbonate (8.6 mg,0.0912 mmol) and the reaction stirred at room temperature for 1H. LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by preparative HPLC (prep. method 1) and after lyophilization, 2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -N- [3- (methylsulfonyl) phenyl ] was obtained as a white solid ]Pyridine-3-carboxamide (100.0%) (8.0 mg,0.0159mmol,52% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (500 mhz, dmso-d 6) delta 10.78 (s, 1H), 8.39 (m, 1H), 8.29 (d, j=2.5 hz, 1H), 8.20 (d, j=2.5 hz, 1H), 7.94 (m, 1H), 7.69-7.66 (m, 1H), 7.65 (d, j=1.9 hz, 1H), 7.59 (t, j=7.9 hz, 1H), 7.51 (dd, j=8.2, 1.9hz, 1H), 7.45 (d, j=8.2 hz, 1H), 6.38 (s, 1H), 4.23 (d, j=2.8 hz, 2H), 4.21 (s, 1H), 3.82 (t, j=5.4 hz, 2H), 3.75 (s, 3H), 3.05 (d, j=1.0 hz, 3H). LC-MS method 6: m/z 505.3[ M+H ]] ⁺ ,(ESI+),RT＝1.11。

Example 99

Compound 1727:2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] -5-tetrahydropyran-4-yl-pyridine-3-carboxamide

Reagents and conditions: a) 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3, 6-dihydro-2H-pyran, pd (OAc) ₂ Dicyclohexyl- [2- (2, 4, 6-triisopropylphenyl) phenyl]Phosphine, na ₃ PO ₄ Dioxane, 80 ℃; b) H ₂ Pd (10%), etOH; c) LiOH, water, THF; d) 3- (methylthio) aniline, EDC, pyridine; e) PIDA, (NH) ₄ ) ₂ CO ₃ 、MeOH

Step 1:2- (4-cyanogen)Methyl-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) -pyridine-3-carboxylate: methyl 5-bromo-2- (4-cyano-2-methoxy-phenoxy) pyridine-3-carboxylate (250 mg,0.688 mmol), dicyclohexyl- [2- (2, 4, 6-triisopropylphenyl) phenyl ]A mixture of phosphine (33 mg,0.0688 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyran (217 mg,1.03 mmol) and tripotassium phosphate (438 mg,2.07 mmol) in 1, 4-dioxane (5 mL) and water (1.5 mL) was degassed with nitrogen for 5 minutes, followed by palladium diacetate (2+) (15 mg,0.0688 mmol). The mixture was heated to 80 ℃ in a pressure flask for 2h. LC-MS analysis indicated completion of the reaction. Dilute with ethyl acetate (20 mL) and wash with water (8 mL) and brine (8 mL). The organics were dried (MgSO 4), filtered and concentrated. Purification by FCC (5 g,0 to 30% ea/heptane) afforded 2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) pyridine-3-carboxylic acid methyl ester (99.0%) as an off-white foam (249 mg,0.673mmol,98% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.30 (d, j=2.3 hz, 1H), 8.22 (d, j=2.6 hz, 1H), 7.34 (dd, j=8.2, 1.8hz, 1H), 7.25-7.21 (m, 2H), 6.17 (m, 1H), 4.32 (q, j=2.8 hz, 2H), 3.96 (s, 3H), 3.94 (t, j=5.5 hz, 2H), 3.76 (s, 3H), 2.52-2.45 (m, 2H). LC-MS method 2: m/z 367.2[ M+H ]] ⁺ ,(ESI+),RT＝0.86。

Step 2:2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid methyl ester: to a solution of methyl 2- (4-cyano-2-methoxy-phenoxy) -5- (3, 6-dihydro-2H-pyran-4-yl) pyridine-3-carboxylate (100 mg,0.273 mmol) in ethanol (2 mL) was applied three vacuum/nitrogen cycles. Palladium (10%, 29mg,0.0273 mmol) was added and three vacuum/nitrogen cycles were applied. The mixture was stirred at room temperature for 4h. LC-MS analysis indicated that the starting material was exhausted. Filtered through celite and concentrated to give a clear oil. Purification by FCC (10 g,0 to 100% ea/heptane) afforded 2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid methyl ester (87.0%) as a white semi-solid (28 mg,0.0661mmol,24% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ8.17(d,J＝2.5Hz,1H),8.07(d,J=2.5 hz, 1H), 7.33 (dd, j=8.2, 1.9hz, 1H), 7.25-7.18 (m, 2H), 4.15-4.04 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.52 (m, 2H), 2.79 (m, 1H), 1.81-1.73 (m, 4H). LC-MS method 2: m/z 369.2[ M+H ]] ⁺ ,(ESI+),RT＝0.83。

Step 3:2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid: to a solution of methyl 2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylate (28 mg,0.0760 mmol) in THF (0.2 mL): water (0.1 mL) was added lithium hydroxide (4.2 mg,0.167 mmol), and the mixture was stirred at room temperature for 2h. LC-MS analysis indicated completion of the reaction. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 5 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give 2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid (90.0%) as a clear oil (25 mg,0.0635mmol,84% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CDCl ₃ ) δ8.37 (d, j=2.2 hz, 1H), 8.13 (d, j=2.5 hz, 1H), 7.46-7.32 (m, 2H), 4.10 (m, 2H), 3.81 (s, 3H), 3.53 (m, 2H), 2.83 (m, 1H), 1.89-1.75 (m, 4H). LC-MS method 2: m/z 355.2[ M+H ] ] ⁺ ,(ESI+),RT＝0.69。

Step 4:2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5-tetrahydropyran-4-yl-pyridine-3-carboxamide: to a solution of 2- (4-cyano-2-methoxy-phenoxy) -5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid (25 mg,0.0705 mmol) and 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (16 mg,0.0847 mmol) in anhydrous pyridine (0.4 mL) was added 3- (methylthio) aniline (12 mg,0.0847 mmol). The mixture was stirred at room temperature for 1h. LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by FCC (5 g,0 to 60% ea/heptane) to give 2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5-tetrahydropyran-4-yl-pyridine-3-carboxamide (87.0%) as an off-white solid (17 mg,0.0311mmol, 44%). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ9.92(s,1H),8.51(d,J＝2.5Hz,1H),8.08(d,J＝2.6Hz,1H),7.98-7.92(m,2H),7.53(m,2H),7.41(dd,J＝8.3,1.8Hz,1H),7.39-7.36(m,1H),7.31(d,J＝1.8Hz,1H),4.10(m,2H),3.89(s,3H),3.60-3.49(m,2H),2.91-2.81(m,1H),2.76(s,3H),1.89-1.79(m,4H)。m/z 476.2[M+H] ⁺ ,(ESI+),RT＝1.01。

Step 5:2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carboxamide: to a solution of 2- (4-cyano-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5-tetrahydropyran-4-yl-pyridine-3-carboxamide (17 mg,0.0357 mmol) in methanol (0.5 mL) was added phenyliodiammonium diacetate (PIDA) (35 mg,0.107 mmol) and diammonium carbonate (10 mg,0.107 mmol) and the reaction was stirred at room temperature for 2h. LC-MS analysis indicated completion of the reaction. The solvent was removed and the residue was purified by preparative HPLC (standard method) and after lyophilization, 2- (4-cyano-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] was obtained as a white solid ]-5-tetrahydropyran-4-yl-pyridine-3-carboxamide (98.0%) (10 mg,0.0193mmol,54% yield). ¹ H NMR and LC-MS analysis indicated this was the desired product. ¹ H NMR (400 mhz, dmso-d 6) δ10.73 (s, 1H), 8.39 (m, 1H), 8.13 (d, j=2.4 hz, 1H), 8.04 (d, j=2.4 hz, 1H), 7.94 (m, 1H), 7.70-7.66 (m, 1H), 7.64 (d, j=1.8 hz, 1H), 7.60 (t, j=7.9 hz, 1H), 7.51 (dd, j=8.2, 1.8hz, 1H), 7.45 (d, j=8.2 hz, 1H), 4.22 (s, 1H), 3.96 (m, 2H), 3.76 (s, 3H), 3.49-3.38 (m, 2H), 3.06 (s, 3H), 2.87 (m, 1H), 1.76-1.67 (m, 4H). LC-MS method 4: m/z 507.2[ M+H ]] ⁺ ,(ESI+),RT＝2.53。

Example 100

Compound 1728: 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy- λ ⁶ Thio group]Phenyl } -4-methylpyridine-3-carboxamide

Reagents and conditions: a) K (K) ₂ CO ₃ 、DMF，100°；b)K ₂ CO ₃ 、H ₂ O ₂ (50%, v/v), DMSO; c) Tert-butyl nitrite, acOH, naOH,70 ℃; d) (S) -N- [ (3-aminophenyl) -methyl-oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate, HATU, DIEA, DMF; e) 2-propanol, 4M HCl/dioxane, 1, 4-dioxane

Step 1: 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carbonitrile

5-bromo-2-chloro-4-methyl-pyridine-3-carbonitrile was prepared as described in WO 2016021742A.

4-fluoro-2-methyl-phenol (1.61 g,12.8 mmol), 5-bromo-2-chloro-4-methyl-pyridine-3-carbonitrile (1.98 g,8.53 mmol) and K ₂ CO ₃ A mixture of (2.36 g,17.1 mmol) in anhydrous DMF (20 mL) was stirred at 100deg.C for 16 hours. The reaction was cooled to room temperature, poured into ice-cold water, and the mixture was extracted with EtOAc (25×3 mL). The combined layers were dried to give a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 20% etoac/heptane afforded 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carbonitrile (100.0%) as a white solid (1.00 g, 36%). 1H NMR (500 MHz, DMSO-d) ₆ ) Delta 8.47 (s, 1H), 7.29-7.18 (m, 2H), 7.16-7.05 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H). m/z:321.0 (Br isotope pattern) [ M+H ]] ⁺ (esi+), rt=4.21 LCMS method 4.

Step 2: 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carboxamide

5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carbonitrile (1.00 g,3.11 mmol) was dissolved in DMSO (17.2 mL) followed by the addition of potassium oxycarbonioxy (1.90 g,13.7 mmol). The reaction mixture was cooled slightly in a water bath. To the reaction mixture was added dropwise a 50% wt aqueous solution of hydrogen peroxide (50%, 1.9ml,34.2 mmol) for 5min (slightly exothermic) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (80 mL) and with HCl (1N) (25 mL). The organic phase was separated with saturated NaHCO ₃ (2X 25 mL) and brine (1X 25 mL), dried and filtered. The solvent was removed under reduced pressure to give 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carboxamide (99.0%) as a white solid (950 mg,2.77mmol, 89%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.19(s,1H),8.08-8.07(m,1H),7.82(d,J＝2.3Hz,1H),7.15(dd,J＝9.4,3.0Hz,1H),7.12-7.02(m,2H),2.36(s,3H),2.08(s,3H)。m/z：339.4 (Br isotope pattern) [ M+H ]] ⁺ (esi+), rt=2.85 LCMS method 4.

Step 3: 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylpyridine-3-carboxylic acid: at N ₂ To a stirred solution of 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carboxamide (170 mg,0.501 mmol) in acetic acid (1.5 mL) was slowly added tert-butyl nitrite (0.18 mL,1.51 mmol) under an atmosphere. The reaction mixture was then stirred at 70 ℃ for 2 hours. After completion, the reaction mixture was evaporated to dryness and NaOH (2M) was added. The aqueous phase was washed with EtOAc (3X 10 mL) and the pH was then adjusted to 1. The aqueous layer had been extracted with EtOAc (3×15 mL), the organic layer was collected and dried to give 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carboxylic acid (89.0%) as an orange solid (154 mg,0.403mmol, 80%). ¹ H NMR(500MHz,DMSO-d ₆ ) δ8.25 (s, 1H), 7.17 (dd, j=9.5, 3.0hz, 1H), 7.10 (dd, j=8.9, 5.2hz, 1H), 7.05 (td, j=8.5, 3.1hz, 1H), 2.38 (s, 3H), 2.05 (s, 3H). m/z:340.0 (Br isotope pattern) [ M+H ] ] ⁺ (esi+), rt=3.25 LCMS method 4.

Step 4: n- [ (S) - {3- [ 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylpyridin-3-amido]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]T-butyl carbamate; N-Ethyl-N- (propan-2-yl) propan-2-amine (195. Mu.L, 1.12 mmol), (S) -N- [ (3-aminophenyl) -methyl-oxo-lambda. ⁶ -a sulfinyl group]A mixture of tert-butyl carbamate (83 mg,0.307 mmol), 5-bromo-2- (4-fluoro-2-methyl-phenoxy) -4-methyl-pyridine-3-carboxylic acid (89%, 107mg,0.280 mmol) in anhydrous DMF (0.56 mL) was stirred for 10 min. HATU (160 mg, 0.426 mmol) was then added. The reaction mixture was stirred at 55 ℃ for 26 hours. The reaction mixture was concentrated in vacuo and subsequently purified via flash chromatography. The fractions containing the desired compound were combined and concentrated to give N- [ (S) - {3- [ 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylpyridin-3-amido) as a white solid]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]Tert-butyl carbamate (139 mg,0.235mmol,84% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.18(s,1H),8.46-8.37(m,1H),8.32(s,1H),7.98-7.90(m,1H),7.70-7.65(m,2H),7.19-7.11(m,2H),7.06(td,J＝8.6,3.1Hz,1H),3.38(s,3H) 2.40 (s, 3H), 2.07 (s, 3H), 1.22 (s, 9H). m/z:492.0 (Br isotope pattern) [ M-BOC+H ]] ⁺ (esi+), rt=0.98 LCMS method 2.

Step 5: 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- {3- [ (S) -imino (meth) oxy- λ ⁶ Thio group]Phenyl } -4-methylpyridine-3-carboxamide. To N- [ (S) - {3- [ 5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methylpyridin-3-yl]Phenyl } (methyl) oxo-lambda ⁶ -a sulfinyl group]To a solution of tert-butyl carbamate (115 mg,0.194 mmol) in anhydrous 1, 4-dioxane (1 mL) and 2-propanol (1 mL) was added 4M hydrogen chloride in dioxane (2.4 mL,9.72 mmol). The mixture was stirred at room temperature overnight. The mixture was then cooled to 0deg.C, diluted with ethyl acetate (20 mL) and saturated NaHCO ₃ The pH was adjusted to about 9. Extracted with ethyl acetate (3X 30 mL) and the organics were dried (MgSO ₄ ) Filtered and concentrated. Purification by flash chromatography gave a white solid (100.0%) (31 mg, 33%). ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.09 (s, 1H), 8.41-8.39 (m, 1H), 8.31 (s, 1H), 7.87 (d, j=8.0 hz, 1H), 7.68 (d, j=7.9 hz, 1H), 7.60 (t, j=7.9 hz, 1H), 7.16 (d, j=4.4 hz, 1H), 7.14 (d, j=4.5 hz, 1H), 7.06 (td, j=8.6, 3.0hz, 1H), 4.22 (s, 1H), 3.06 (s, 3H), 2.41 (s, 3H), 2.08 (s, 3H). m/z:492.0 (Br isotope pattern) [ M+H ]] ⁺ (esi+), rt=2.98 LCMS method 4.

Example 101

Compound 1729:2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: a) 3- (methylthio) aniline, HATU, DIEA, DMF; b) Bis (acetoxy) iodobenzene, (NH) ₄ ) ₂ CO ₃ MeOH; c) 3, 4-difluoro-2-methoxy-phenol, K ₂ CO ₃ Acetonitrile, 70 ℃.

Step 1: 2-chloro-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide

To 2-chloro-6- (trifluoro)To a mixture of methyl) pyridine-3-carboxylic acid (300 mg,1.33 mmol), HATU (607 mg,1.60 mmol) and DIPEA (460 uL,2.66 mmol) in DMF (3.6 mL) was added 3- (methylthio) aniline (197uL, 1.60 mmol). The reaction mixture was stirred at room temperature for 17h, then poured into water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were washed with 5% aqueous licl (2×10 mL), dried over MgSO4 and concentrated under reduced pressure to give 737mg of brown gum. The crude product was purified by FCC (Biotage Isolera 4, 25g Sfar Duo, lambda-all collected) using a 0-100% etoac/heptane gradient to give 2-chloro-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide (97.0%) as a pale yellow solid (277 mg, 58%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.79(br.s,1H),8.42(d,J＝7.5Hz,1H),8.13(d,J＝7.8Hz,1H),7.66(t,J＝1.9Hz,1H),7.42(ddd,J＝8.1,1.9,0.9Hz,1H),7.33(t,J＝7.9Hz,1H),7.05(ddd,J＝7.8,1.7,0.9Hz,1H),2.48(s,3H)。

m/z：347.0,349.0[M+H] ⁺ (esi+), rt=0.93 LCMS method 2.

Step 2: 2-chloro-N- [3- (methylsulfonyl) phenyl ]]-6- (trifluoromethyl) pyridine-3-carboxamide: to a solution of 2-chloro-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide (97%, 277mg,0.775 mmol) in methanol (11 mL) was added bis (acetoxy) iodobenzene (514 mg,1.78 mmol) and ammonium carbonate (109 mg,1.16 mmol), and the reaction was stirred at room temperature for 16h. The reaction mixture was then diluted with DCM, dried loaded onto silica and purified by column chromatography using 0 to 100% EtOAc/heptane, 0-20% meoh/EtOAc (on a Biotage Sfar Duo 10g column, lambda-all collected) in sequence to give 2-chloro-N- [3- (methylsulfonyl) phenyl as a beige powder ]-6- (trifluoromethyl) pyridine-3-carboxamide (95.0%) (272 mg, 88%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.11(s,1H),8.45(d,J＝7.5Hz,1H),8.34(t,J＝1.9Hz,1H),8.15(d,J＝7.8Hz,1H),7.89(ddd,J＝8.0,2.0,1.0Hz,1H),7.72(dt,J＝7.8,1.1Hz,1H),7.63(t,J＝7.9Hz,1H),4.25(s,1H),3.07(s,3H)。m/z：378.1,380.0[M+H] ⁺ (esi+), rt=0.68 LCMS method 2.

Step 3:2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]-6- (tri)Fluoromethyl) pyridine-3-carboxamide: 2-chloro-N- [3- (methylsulfonyl) phenyl ]]A mixture of 6- (trifluoromethyl) pyridine-3-carboxamide (120 mg,0.318 mmol), 3, 4-difluoro-2-methoxy-phenol (56 mg,0.349 mmol) and potassium carbonate (66 mg,0.476 mmol) in anhydrous acetonitrile (2.4 mL) was stirred at 60℃for 17h. The reaction mixture was cooled, diluted with MeCN (2 mL), filtered through a phase separator and the solid was washed with MeCN (2 x 2 mL). The combined filtrates were concentrated under reduced pressure to give 183mg of a yellow gum. The crude compound was purified by preparative HPLC (prep. method 1). The product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to give 2- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] as a white powder]-6- (trifluoromethyl) pyridine-3-carboxamide (99.0%) (129 mg, 80%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.01(s,1H),8.45-8.36(m,2H),7.96-7.89(m,1H),7.82(d,J＝7.6Hz,1H),7.69(dt,J＝7.9,1.2Hz,1H),7.61(t,J＝7.9Hz,1H),7.32-7.18(m,2H),4.24(s,1H),3.81-3.73(m,3H),3.06(s,3H)。m/z：502.0[M+H]+, (esi+), rt=3.40 LCMS method 4.

Compound 1730: (R) -2- (4-cyano-2-methoxyphenoxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) nicotinamide

Reagents and conditions: a) NaOEt/EtOH,85 ℃; b) POCl (Point of care testing) ₃ 、Et ³ N.hcl,105 ℃; c) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ 、NMP，100℃；d)LiOH、THF/H ₂ O; e) (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate, oxalyl chloride, DCM, DMF, DIEA; f) 4M HCl/dioxane, 1, 4-dioxane, 2-propanol, room temperature.

Step 1: 4-methyl-2-oxo-6- (trifluoromethyl) -1H-pyridine-3-carboxylic acid ethyl ester: to a solution of ethyl carbamoylacetate (1.56 g,11.9 mmol) and (E) -1, 1-trifluoro-4-methoxy-pent-3-en-2-one (2.00 g,11.9 mmol) in ethanol (20 mL) was added ethanol(21%, 23mL,61.8 mmol) and the mixture was heated at 85deg.C for 17h. 2M aqueous HCl was added to the reaction mixture at room temperature until pH 5 and volatiles were removed under reduced pressure. The remaining aqueous solution was extracted with EtOAc (3X 30 mL) and the combined organics were washed with brine (30 mL) over MgSO ₄ Dried and concentrated under reduced pressure to give 4-methyl-2-oxo-6- (trifluoromethyl) -1H-pyridine-3-carboxylic acid ethyl ester (86.0%) as a brown free-flowing oil (1.49 g,5.14mmol, 43%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.36(br.s,1H),7.31(s,1H),4.32(q,J＝7.1Hz,2H),2.30(s,3H),1.28(t,J＝7.1Hz,3H)。m/z：250.1[M+H] ⁺ (esi+), rt=0.75 LCMS method 2

Step 2: 2-chloro-4-methyl-6- (trifluoromethyl) pyridine-3-carboxylic acid ethyl ester: a mixture of ethyl 4-methyl-2-oxo-6- (trifluoromethyl) -1H-pyridine-3-carboxylate (86%, 750mg,2.59 mmol), trimethylamine hydrochloride (1:1) (371 mg,3.88 mmol) and phosphorus oxychloride (6.0 mL,64.2 mmol) was stirred in a reduced pressure vial at 105℃for 17H. The reaction mixture was cooled and then treated again with phosphorus oxychloride (2.0 mL,21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg,1.29 mmol). Heating was resumed at 105℃for 18 hours. The reaction mixture was treated again with phosphorus oxychloride (2.0 mL,21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg,1.29 mmol) at room temperature. Heating was resumed at 105℃for 18 hours. The cooled reaction mixture was added dropwise to water and saturated Na ₂ CO ₃ Aqueous solution in a stirred solution (1:1, 50 mL). By careful addition of solid Na ₂ CO ₃ The mixture was neutralized and the product was then extracted with DCM (3X 50 mL). The combined organics were dried using a phase separation cartridge and concentrated under reduced pressure to give ethyl 2-chloro-4-methyl-6- (trifluoromethyl) pyridine-3-carboxylate (87.0%) as a dark brown free-flowing oil (425 mg,1.38mmol, 53%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(s,1H),4.45(q,J＝7.1Hz,2H),2.44(s,3H),1.34(t,J＝7.1Hz,3H)。m/z：268.0,270.0[M+H] ⁺ (esi+), rt=0.97 LCMS method 2.

Step 3:2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxylic acid ethyl ester: 2-chloro-4-methyl-6- (trifluoromethyl) pyri-dineA mixture of ethyl pyridine-3-carboxylate (79%, 208mg,0.614 mmol), 4-hydroxy-3-methoxybenzonitrile (137 mg,0.921 mmol) and potassium carbonate (255 mg,1.84 mmol) in anhydrous NMP (2.5 mL) was stirred at 100deg.C in an Ace pressure tube for 22h. The reaction mixture was cooled to room temperature, then diluted with DCM (15 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with DCM (2X 15 mL). The combined organics were dried using a phase separator and concentrated under reduced pressure to give a brown free-flowing oil. The crude product was purified by FCC (Biotage Isolera,10g Sfar Duo cartridge, lambda-all collected) using a 0-25% etoac/heptane gradient. The product fractions were combined and concentrated under reduced pressure to give ethyl 2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxylate (35.0%) as a yellow free-flowing oil (571 mg,0.525mmol, 86%). 65% NMP w/w ¹ HNMR(400MHz,DMSO-d ₆ )δ7.71-7.67(m,2H),7.50(dd,J＝8.2,1.8Hz,1H),7.38(d,J＝8.2Hz,1H),4.40(q,J＝7.1Hz,2H),3.73(s,3H),2.45(s,3H),1.30(t,J＝7.1Hz,3H)。m/z：381.1[M+H] ⁺ (esi+), rt=1.01 LCMS method 2

Step 4:2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxylic acid: to a mixture of ethyl 2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxylate (42%, 571mg,0.631 mmol) in THF (3 mL) -water (1.5 mL) was added lithium hydroxide (45 mg,1.89 mmol) and the mixture was stirred at room temperature for 16h. The reaction mixture was treated again with lithium hydroxide (45 mg,1.89 mmol) and stirring was continued for 5h at room temperature. Methanol (0.2 mL) was added to the reaction mixture and stirring was continued for 17 hours at room temperature. The reaction mixture was treated again with lithium hydroxide (45 mg,1.89 mmol) and stirred for a further 22h. The reaction mixture was diluted with water (15 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl, followed by extraction with EtOAc (3×10 mL), drying using a phase separator and concentration in vacuo afforded 256mg of a pale yellow gum. The crude product was purified by FCC (Biotage Isolera4, 10g Sfar Duo, lambda-all collected) using a 0-100% EtOAC/heptane gradient and rinsing with 0-60% meoh/EtOAC. The product fractions were combined and concentrated under reduced pressure to give 2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- "as a white powder Trifluoromethyl) pyridine-3-carboxylic acid (99.0%) (108 mg,0.304mmol, 48%). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 7.68 (d, j=1.8 hz, 1H), 7.64 (s, 1H), 7.50 (dd, j=8.2, 1.9hz, 1H), 7.36 (d, j=8.2 hz, 1H), 3.73 (s, 3H), 2.45 (s, 3H). No acid protons m/z were observed: 353.1[ M+H ]] ⁺ (esi+), rt=0.81 LCMS method 2.

Step 5: (R) - ((3- (2- (4-cyano-2-methoxyphenoxy) -4-methyl-6- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda ⁶ -sulfoanyl) carbamic acid tert-butyl ester

To a stirred solution of 2- (4-cyano-2-methoxy-phenoxy) -4-methyl-6- (trifluoromethyl) pyridine-3-carboxylic acid (99%, 105mg,0.295 mmol) in anhydrous DCM (1.3 mL) under nitrogen at room temperature was added anhydrous DMF (4.6 uL,0.0590 mmol) followed by oxalyl chloride (28 uL,0.325 mmol). The reaction was stirred for 50 minutes. (R) - ((3-aminophenyl) (methyl) (oxo) -lambda was then added to anhydrous DCM (0.5 mL) ⁶ Tert-butyl sulfinyl) carbamate (86%, 111mg,0.354 mmol) followed by DIPEA (103 ul, 0.560 mmol) and the reaction was stirred at room temperature for 1h. Water (2 mL) was added to the reaction and the mixture passed through a phase separator and rinsed with DCM (3X 3 mL). The combined organic phases were concentrated in vacuo to give 227mg of a pale yellow foam. The crude product was purified by FCC, silica using 0-100% EtOAc/heptane and rinsed with 0-20% meoh/EtOAc (on a Biotage Sfar Duo 10g column), and concentrated in vacuo to give (R) - ((3- (2- (4-cyano-2-methoxyphenoxy) -4-methyl-6- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) - λ) as an off-white solid ⁶ Tert-butyl (89.0%) (171 mg,0.252mmol, 85%). m/z:505.1[ M-BOC+H] ⁺ (esi+), rt=0.94 LCMS method 2

Step 6: (R) -2- (4-cyano-2-methoxyphenoxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) nicotinamide: to (R) - ((3- (2- (4-cyano-2-methoxyphenoxy) -4-methyl-6- (trifluoromethyl) nicotinamide) phenyl) (methyl) (oxo) -lambda ⁶ To a solution of tert-butyl (89%, 168mg,0.247 mmol) of sulfoalkyl) carbamate in anhydrous 1, 4-dioxane (1.4 mL) and 2-propanol (1.4 mL) was added 4M HCl/dioxane (3.1 mL,12.4 mmol) and the mixture was stirred at room temperature for 1 hour 15 min. The reaction mixture was then cooled to 0deg.C, diluted with EtOAc (20 mL) and saturated NaHCO ₃ The aqueous solution was alkalized to pH 9. The layers were separated and the aqueous phase extracted with EtOAc (2X 15 mL). The combined organics were dried over MgSO ₄ Dried and concentrated to dryness under vacuum to give 206mg of a pale yellow crude residue. The crude material was purified by acidic (0.1% formic acid) reverse phase chromatography (Sfar C18 g D duo,10-100% mecn/water). The pure product fractions were concentrated under reduced pressure and the resulting residue was freeze-dried from MeCN-water (1:1) to give (R) -2- (4-cyano-2-methoxyphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) nicotinamide (97.0%) as a white powder (88 mg,0.169mmol, 68%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.09(s,1H),8.40(t,J＝1.9Hz,1H),7.88(ddd,J＝8.1,2.0,1.0Hz,1H),7.72(s,1H),7.71-7.67(m,2H),7.60(t,J＝7.9Hz,1H),7.51(dd,J＝8.2,1.9Hz,1H),7.41(d,J＝8.2Hz,1H),4.22(s,1H),3.75(s,3H),3.09-3.04(m,3H),2.48(s,3H)。m/z：505.1[M+H] ⁺ (esi+), rt=2.89 LCMS method 4.

Compound 1731: (R) -5-bromo-2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methanesulfonyl) phenyl) nicotinamide.

The title compound was prepared by a procedure similar to that described for compound 1728 using the appropriate starting materials. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.10(s,1H),8.41(t,J＝1.9Hz,1H),8.31(s,1H),7.91-7.84(m,1H),7.75-7.66(m,1H),7.60(t,J＝7.9Hz,1H),7.19-7.12(m,2H),7.06(td,J＝8.4,3.1Hz,1H),4.23(s,1H),3.07-3.04(m,3H),2.41(s,3H),2.08(s,3H)。m/z：492.0-494.0[M+H] ⁺ (esi+), rt=2.98 LCMS method 4.

Compound 1732: (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -5- (piperidin-1-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide.

The title compound was prepared by a procedure similar to that described for compound 1522 using the appropriate starting materials. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.24(s,1H),8.31(t,J＝1.9Hz,1H),7.87(ddd,J＝8.1,2.2,1.1Hz,1H),7.72(dt,J＝8.0,1.3Hz,1H),7.64(t,J＝7.9Hz,1H),7.29-7.16(m,2H),7.11(td,J＝8.7,3.3Hz,1H),4.27(d,J＝1.3Hz,1H),3.25-3.17(m,4H),3.07(d,J＝1.1Hz,3H),2.12(s,3H),1.64-1.43(m,6H)。m/z：552.1[M+H] ⁺ (esi+), rt=3.48 LCMS method 4.

Compound 1733: (R) -3- (4-cyano-2-methoxyphenoxy) -6- (6-methoxypyridin-3-yl) -5-methyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 1531 using the appropriate starting materials. ¹ H NMR(400MHz,MeOD)δ6.92(t,J＝2.0Hz,1H),6.81(m,1H),6.43(m,1H),6.36(dd,J＝8.6,2.5Hz,1H),6.29(m,1H),6.11(t,J＝8.0Hz,1H),5.98(d,J＝1.5Hz,1H),5.93-5.85(m,2H),5.42(m,1H),2.45(s,3H),2.28(s,3H),1.63(s,3H),0.91(s,3H)。m/z：545.1[M+H] ⁺ (esi+), rt=2.46 LCMS method 4.

Compound 1734: (R) N- [3- (N-acetyl-S-methyl-sulfinyl) phenyl ] -3- (4-cyano-2-methoxy-phenoxy) -5-methyl-6- (p-tolyl) pyridazine-4-carboxamide

The title compound (R) -3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (p-tolyl) pyridazine-4-carboxamide was prepared. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.38(s,1H),8.43-8.39(m,1H),7.95(dt,J＝6.8,2.1Hz,1H),7.73-7.66(m,3H),7.55(dd,J＝8.2,1.8Hz,1H),7.52-7.43(m,3H),7.36(d,J＝7.9Hz,2H),3.81(s,3H),3.43(s,3H),2.40(s,3H),2.35(s,3H),1.98(s,3H)。m/z：570.1[M+H] ⁺ (esi+), rt=3.14 LCMS method 4.

Compound 1735: (R) -3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (o-tolyl) pyridazine-4-carboxamide.

¹ H NMR(400MHz,CD ₃ OD)δ8.46(t,J＝2.0Hz,1H),7.98(m,1H),7.83(m,1H),7.66(t,J＝8.0Hz,1H),7.52(d,J＝1.8Hz,1H),7.49-7.31(m,5H),7.24(m,1H),3.83(s,3H),3.17(s,3H),2.21(s,3H),2.13(s,3H)。m/z：528.2[M+H] ⁺ (esi+), rt=2.79 LCMS method 4

Compound 1736: (R) -3- ((6-cyano-2-methoxypyridin-3-yl) oxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.32(s,1H),8.34(t,J＝1.9Hz,1H),8.01(d,J＝7.9Hz,1H),7.90-7.86(m,1H),7.84(d,J＝7.9Hz,1H),7.76-7.71(m,1H),7.65(d,J＝7.9Hz,1H),4.27(d,J＝1.2Hz,1H),3.88(s,3H),3.08(d,J＝1.1Hz,3H),2.54-2.52(m,3H)。

m/z：507.3[M+H] ⁺ (esi+), rt=2.95 LCMS method 4.

Compound 1737: (R) -3- ((6-cyano-2-methylpyridin-3-yl) oxy) -5-methyl-N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

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¹ H NMR(400MHz,DMSO-d ₆ )δ11.39(s,1H),8.35(t,J＝1.9Hz,1H),8.10-8.03(m,2H),7.87(ddd,J＝8.0,2.2,1.1Hz,1H),7.77-7.71(m,1H),7.64(t,J＝7.9Hz,1H),4.27(s,1H),3.11-3.02(m,3H),2.57-2.54(m,3H),2.41(s,3H)。m/z：491.4[M+H] ⁺ (esi+), rt=2.73 LCMS method 4.

Compound 1738: (R) -3- (4-cyano-2-methoxyphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.21(s,1H),8.69(s,1H),8.34(t,J＝1.9Hz,1H),7.93(ddd,J＝8.0,2.2,1.1Hz,1H),7.78-7.69(m,2H),7.64(t,J＝7.9Hz,1H),7.58(d,J＝1.0Hz,2H),4.26(s,1H),3.78(s,3H),3.07(s,3H)。m/z：492.4[M+H] ⁺ (esi+), rt=2.84 LCMS method 4.

Compound 1739: (R) -3- (4-cyano-2-methoxyphenoxy) -5-methyl-N- (3- (S-methyl-N- (methylglycyl) sulphonimidoyl) phenyl) -6- (p-tolyl) pyridazine-4-carboxamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.42(s,1H),8.44(s,1H),7.93(d,J＝7.4Hz,1H),7.80-7.60(m,3H),7.54(dd,J＝8.2,1.7Hz,1H),7.51-7.40(m,3H),7.35(d,J＝8.0Hz,2H),3.80(s,3H),3.71-3.66(m,1H),3.45(s,3H),3.18(s,2H),2.39(s,3H),2.34(s,3H),2.21(s,3H)。

m/z：599.1[M+H] ⁺ (esi+), rt=2.16 LCMS method 2.

Compound 1740: (R) -5- (4-cyanophenyl) -2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) nicotinamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.13(s,1H),8.46(t,J＝2.0Hz,1H),8.05(s,1H),8.01-7.94(m,2H),7.91-7.86(m,1H),7.71-7.65(m,1H),7.64-7.56(m,3H),7.27-7.14(m,2H),7.08(td,J＝8.5,3.1Hz,1H),4.23-4.21(m,1H),3.09-2.98(m,3H),2.28(s,3H),2.13(s,3H)。m/z：515.2[M+H] ⁺ (esi+), rt=3.06 LCMS method 4.

Compound 1741: (S) -5- (4-cyanophenyl) -2- (4-fluoro-2-methylphenoxy) -4-methyl-N- (3- (S-methylsulfonyl) phenyl) nicotinamide

¹ H NMR(400MHz,DMSO-d ₆ )δ11.13(s,1H),8.45(t,J＝1.9Hz,1H),8.05(s,1H),7.99-7.94(m,2H),7.91-7.87(m,1H),7.70-7.66(m,1H),7.64-7.57(m,3H),7.22-7.14(m,2H),7.07(td,J＝8.6,3.2Hz,1H),4.23-4.21(m,1H),3.12-3.02(m,3H),2.28(s,3H),2.12(s,3H)。m/z：515.2[M+H] ⁺ (esi+), rt=3.06 LCMS method 4.

Compound 1742: n- (3-carbamoylphenyl) -4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxamide

Reagents and conditions: a) EtOH,90 ℃; b) 1-bromopyrrolidine-2, 5-dione, alpha-benzotrifluoride, K ₂ CO ₃ 70 ℃; c) 2, 2-trichloroacetonitrile, triphenylphosphine, toluene, and 100deg.C; d) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ Acetonitrile, 60 ℃; e) LiOH, THF/H ₂ O; e) 3-aminobenzamide, HATU, DIEA, DMF.

Step 1: 6-methyl-4-oxo-2- (trifluoromethyl) -5, 6-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester: 2, 2-Trifluoroacetamidine (0.40 mL,4.46 mmol) and diethyl ethylenemalonate (0.90 mL,4.91 mmol) were dissolved in ethanol (5 mL) and heated in a pressure tube at 90℃for 2 hours. Concentrating the mixtureAnd the residue was dissolved in water (10 mL). The pH was adjusted to 4 with 1M HCl followed by extraction with ethyl acetate (3X 10 mL). The organics were dried, filtered and concentrated to give a yellow oil. Purification by FCC (EtOAc/DCM) afforded 6-methyl-4-oxo-2- (trifluoromethyl) -5, 6-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester (90.0%) as a yellow oil (284 mg,1.02mmol,21% yield). 1H-19F-NMR and LCMS analysis indicated this was the desired product, about 8:1 isomer mixture. ¹ H NMR(400MHz,CDCl ₃ )δ8.57(s,1H),4.36-4.14(m,3H),3.28(d,J＝8.8Hz,1H),1.39(d,J＝6.9Hz,3H),1.29(t,J＝7.1Hz,3H)。m/z：253.1[M+H] ⁺ (esi+), rt=0.63 LCMS method 2.

Step 2: 6-methyl-4-oxo-2- (trifluoromethyl) -1H-pyrimidine-5-carboxylic acid ethyl ester: 6-methyl-4-oxo-2- (trifluoromethyl) -5, 6-dihydro-1H-pyrimidine-5-carboxylic acid ethyl ester (1.33 g,5.29 mmol), 2' - (E) -diazene-1, 2-diylbis (2-methylpropanenitrile) (0.043 g,0.264 mmol), 1-bromopyrrolidine-2, 5-dione (1.32 g,7.41 mmol) and K ₂ CO ₃ (7.31 g,52.9 mmol) in α, α, α -benzotrifluoride (40 mL) was heated in a pressure flask at 70deg.C for 1h. LCMS analysis indicated reaction was complete. The mixture was filtered through cotton wool, further eluted with MeCN, and concentrated to give an orange oil. Purification by FCC (25 g,0 to 100% EA/DCM followed by 0 to 15% meoh/EA) afforded 6-methyl-4-oxo-2- (trifluoromethyl) -1H-pyrimidine-5-carboxylic acid ethyl ester (91.0%) as a yellow oil (0.60 g,2.19mmol,41% yield). ¹ H NMR(400MHz,CDCl ₃ )δ4.49(m,2H),2.78(s,3H),1.45(t,J＝7.2Hz,3H)。m/z：251.1[M+H] ⁺ (esi+), rt=0.68 LCMS method 2.

Step 3: 4-chloro-6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester: to a solution of ethyl 6-methyl-4-oxo-2- (trifluoromethyl) -1H-pyrimidine-5-carboxylate (412 mg,1.65 mmol) and triphenylphosphine (1296 mg,4.94 mmol) in anhydrous toluene (10 mL) was added 2, 2-trichloroacetonitrile (0.25 mL,2.47 mmol). The mixture was heated at 100℃for 0.5 h. Filtration and concentration gave ethyl 4-chloro-6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylate (11.0%) as a brown oil (2402 mg,0.984mmol,60% yield). Which is used directly in the next step. m/z:5 38.3[2M+H] ⁺ (esi+), rt=1.00 LCMS method 2.

Step 4:4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester: to a solution of 4-chloro-6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester (442 mg,1.65 mmol) and 4-hydroxy-3-methoxybenzonitrile (295 mg,1.97 mmol) in acetonitrile (10 mL) was added K ₂ CO ₃ (45 mg,3.29 mmol). The mixture was stirred at 60℃for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3X 20 mL). The combined organics were dried (MgSO ₄ ) Filtration and concentration gave a brown oil. Purification by FCC (25 g,0 to 100% ea/heptane) afforded 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester (84.0%) as a pale yellow solid (323 mg, 0.719mmol, 43% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.34(dd,J＝8.2,1.8Hz,1H),7.24(d,J＝1.9Hz,2H),4.49(q,J＝7.1Hz,2H),3.77(s,3H),2.67(s,3H),1.42(t,J＝7.1Hz,3H)。m/z：382.2[M+H] ⁺ (esi+), rt=1.04 LCMS method 2.

Step 5:4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid: to a solution of 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester (323 mg,0.847 mmol) in THF (2.5 mL): water (0.5 mL) was added lithium hydroxide (47 mg,1.86 mmol), and the mixture was stirred at 40 ℃ for 2 hours, followed by overnight at room temperature. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl (aqueous solution). The aqueous layer was extracted with EtOAc (3X 8 mL) and dried (MgSO ₄ ) Filtered and concentrated in vacuo to give a yellow oil. Purification by FCC (10 g,0 to 20% meoh/EA) afforded 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid (323 mg,0.847 mmol) as a pale yellow foam. ¹ H NMR(400MHz,CDCl ₃ )δ7.36(dd,J＝8.2,1.8Hz,1H),7.28(d,J＝8.3Hz,1H),7.25(m,1H),3.78(s,3H),2.79(s,3H)。m/z：354.2[M+H]+, (esi+), rt=0.76 LCMS method 2

Step 6: n- (3-carbamoylphenyl) -4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxamide: to the direction ofTo a solution of 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid (60 mg,0.170 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.059 mL,0.340 mmol) in anhydrous DMF (1.2 mL) was added N- [ (dimethylamino) (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-N-methyl ammonium hexafluorophosphate (77 mg,0.204 mmol). The mixture was stirred at room temperature for 5 minutes, then 3-aminobenzamide (98%, 31mg,0.221 mmol) was added. The mixture was stirred at room temperature for 1h. LCMS analysis indicated reaction was complete. The mixture was diluted with ethyl acetate (8 mL) and washed with water (3×4 mL) and brine (4 mL). The organics were dried (MgSO ₄ ) Filtered and concentrated to give an orange oil. Purification by preparation 2 gave N- (3-carbamoyl-phenyl) -4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxamide (100.0%) as a white solid (44 mg,0.0933mmol,55% yield). ¹ H NMR(400MHz,CD ₃ OD)δ8.18(t,J＝1.9Hz,1H),7.91(m,1H),7.68(m,1H),7.54(d,J＝1.6Hz,1H),7.50(t,J＝7.9Hz,1H),7.46-7.39(m,2H),3.81(s,3H),2.69(s,3H)。m/z：472.5[M+H] ⁺ (esi+), rt=2.94 LCMS method 4.

Compound 1743:4- (4-cyano-2-methoxy-phenoxy) -6-methyl-N- [3- (methylsulfonyl) phenyl ] -2- (trifluoromethyl) pyrimidine-5-carboxamide

The title compound was prepared using 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid and the appropriate substituted aniline. ¹ H NMR(400MHz,CD ₃ OD)δ8.45(t,J＝2.0Hz,1H),7.98(m,1H),7.83(m,1H),7.66(t,J＝8.0Hz,1H),7.54(d,J＝1.7Hz,1H),7.47-7.37(m,2H),3.81(s,3H),3.17(s,3H),2.69(s,3H)。m/z：506.5[M+H] ⁺ (esi+), rt=2.93 LCMS method 4.

Compound 1744: n- (4-carbamoylphenyl) -4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxamide

The title compound was prepared using 4- (4-cyano-2-methoxy-phenoxy) -6-methyl-2- (trifluoromethyl) pyrimidine-5-carboxylic acid and 4-aminobenzamide using the coupling conditions described above. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.05(s,1H),7.95-7.87(m,3H),7.78-7.71(m,3H),7.56(dd,J＝8.2,1.8Hz,1H),7.50(d,J＝8.2Hz,1H),7.31(s,1H),3.78(s,3H),2.63(s,3H)。m/z：472.2[M+H] ⁺ (esi+), rt=2.86 MET-uPLC-AB-101 (7 min, low pH).

Example 102

For Na _V 1.8 Compound Profile-human Na _V 1.8 cell line-SyncroPatch 384PE assay

Recombinant Na using SyncroPatch384PE system (automated patch clamp apparatus) _V 1.8 stably transfected HEK cells test compound. Cells at 37℃C/5% CO ₂ The culture was performed in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS10% and inoculated in T175 flasks. Cells were cultured at 30 ℃ the day before recording sodium current. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium and placed in a syncopatch 384PE 6 ℃ pre-cooled cell hotel and shaken at 200 rpm. The intracellular solution (IC) contains the following in mM: 10, cscl;110, csf;20, EGTA;10, HEPES. The extracellular solution (EC) contained the following in mM: 140, naCl;4, KCl;5, glucose; 10, HEPES;2, caCl ₂ ；1，MgCl ₂ . The wash solution contained the following in mM: 40, nmdg;100, naCl;4, KCl;10, glucose; 10, HEPES;5, caCl ₂ ；1，MgCl ₂ 。

Compounds were tested in triplicate in 0.1% dmso and 0.03% Pluronic Acid (Pluronic Acid). The compounds were diluted 1:3 in EC solution to generate a 10 point concentration response curve spanning a final concentration range of 20-0.001 μm in the assay plate. Each plate contained tetracaine and another tool compound as positive controls. Up to 8 compounds were tested on one plate. 250. Mu.M tetracaine and 0.1% DMSO were used as high and low controls, respectively.

According to the Nanion pairWhole cell patch clamp recordings were performed according to standard procedures of (2). The cells were held at a holding potential of-120 mV. A depolarization step of 10mV was applied for 30ms (P1 measurement), followed by a hyperpolarization step to-100 mV for 100ms. An inactivation step of 10 seconds was applied at-40 mV before stepping to-100 mV for 20ms, then stepping to 10mV for 30ms (P2 measurement), and then returning to-100 mV for 30ms. The scan interval was 15 seconds and the sampling rate was 10kHz. After establishment of the whole cell configuration in EC, two wash steps were performed with reference buffer to stabilize the baseline. The compound was then applied to each well by SynchroPatch and the current was recorded in EC for five minutes, followed by the application of tetracaine to obtain complete blocks at the end of the experiment. The efficacy of the compounds was evaluated for two readings (resting state block (P1 measurement) or inactive state block (P2 measurement)) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) control values. The IC50 values are as follows in table 16: "A" means an IC50 of less than or equal to 20nM, "B" means an IC50 of greater than 20nM to less than or equal to 40nM, "C" means an IC50 of greater than 40nM to less than or equal to 200nM, and "D" means an IC50 of greater than 200nM to less than or equal to 500 nM. / >

Table 16

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ND-not measured

B. Examples of the second group of Compounds

Example 103

Compound 1:2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. Times.) amino group ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide

Reagents and conditions: liOH.H ₂ O, THF/H2O, room temperature; b) 3- [ (] ² H ₃ ) Methylthio radical]Aniline, HATU, DIEA, DMF; c) PIDA, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature.

Step 1:2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid: to a solution of methyl 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) pyridine-3-carboxylate (8.80 g,26.1 mmol) in THF: water (33.4 mL;5:1 v/v) was added LiOH. H at room temperature ₂ O (5.61 g,134 mmol). The resulting mixture was stirred at room temperature for an additional 3h. At the end of this period the solvent was evaporated, water (20 mL) was added to the residue and acidified with 1N HCl. The isolated solid was filtered and washed with water (2X 20 mL) to give 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (7.6 g, 90%). ¹ H NMR(300MHz,CDCl ₃ )δ8.63(dd,J＝2.6,0.7Hz,1H),8.47(dq,J＝2.7,0.9Hz,1H),7.03-6.84(m,3H),2.09(s,3H)。

Step 2:2- (4-fluoro-2-methylphenoxy) -N- {3- [ ((d-i-x) -N- [) ² H ₃ ) Methylthio radical]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide: to 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid (6.0 g,19.0 mmol), 3- [. Sup. ² H ₃ ) Methylthio radical]To a mixture of aniline (2.98 g,20.9 mmol) in DMF (30 mL) was added HATU (10.9 g,28.6 mmol) followed by DIEA (7.38 g,57.1 mmol). The resulting mixture was stirred at room temperature for 16 hours. At the end of this period, water (30 mL) was added and extracted with EtOAc (2X 40 mL). The EtOAc layer was washed with water (30 mL) and brine (30 mL) and the organic layer was dried over Na ₂ SO ₄ Dried, filtered, and the solvent evaporated. The crude material was purified on SiO with a gradient of 0 to 30% EtOAc in hexane ₂ Chromatographic analysis is carried out on the mixture to obtain the 2- (4-fluoro-2-methylphenoxy) -N- {3- [ ((N-4-fluoro-2-methylphenoxy) -N- {3- [) ² H ₃ ) Methylthio radical]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide (7.80 g, 93%). ¹ H NMR(300MHz,CDCl ₃ )δ9.63(s,1H),8.92-8.87(m,1H),8.41(dq,J＝1.8,0.9Hz,1H),7.65(t,J＝1.9Hz,1H),7.29-7.16(m,2H),7.09-6.92(m,4H),2.13(s,3H)。

Step 3:2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. Times.) amino group ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide: to 2- (4-fluoro-2-methylphenoxy) -N- {3- [ (-, at room temperature ² H ₃ ) Methylthio radical]To a solution of phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide (7.80 g,17.7 mmol) in MeOH (150 mL) was added ammonium carbonate (2.56 g,26.6 mmol) and PIDA (13.1 g,40.8 mmol). The mixture was stirred at room temperature for 16h. At the end of this period, the solvent was evaporated, the crude was dissolved in EtOAc (150 mL) and washed with saturated NaHCO3 solution, etOAc layer was purified over Na ₂ SO ₄ Dried, filtered, and the solvent evaporated. The crude mixture was purified on SiO with a gradient of 0 to 10% MeOH/DCM ₂ Chromatographic analysis is carried out on the mixture to obtain 2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (. Times.) A. In the prior art ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide (6.02 g, 72%). ¹ H NMR(300MHz,DMSO-d ₆ )δ10.98(s,1H),8.67(dt,J＝2.5,1.1Hz,1H),8.61-8.52(m,1H),8.39(t,J＝1.9Hz,1H),7.95(dt,J＝8.2,1.4Hz,1H),7.75-7.56(m,2H),7.34-7.06(m,3H),4.25(s,1H),2.10(s,3H)。

Example 104

Compounds 2 and 3: (S) -2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. Times.) amino group ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide and (R) -2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. DELTA. ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide

2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. Times.) ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]The racemic mixture of phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide was isolated using the following chiral purification method: mobile phase: 20% methanol 80% CO ₂ The method comprises the steps of carrying out a first treatment on the surface of the Column: chiralpak AD-H, 10X 250mm,5 μm. Flow rate: 15ml/min. The first eluting isomer (S) -2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (. Times.) ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide (S) -2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-. DELTA. ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group ]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide. ¹ H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.66(dd,J＝2.4,1.0Hz,1H),8.57-8.51(m,1H),8.38(t,J＝1.8Hz,1H),7.96-7.90(m,1H),7.71-7.65(m,1H),7.61(t,J＝7.9Hz,1H),7.27(dd,J＝8.9,5.1Hz,1H),7.20(dd,J＝9.5,3.0Hz,1H),7.11(td,J＝8.5,3.1Hz,1H),4.21(s,1H),2.09(s,3H)。m/z 471.5[M+H] ⁺ (esi+), rt=4.04 LC-MS method 5 and the second eluting isomer (R) -2- (4-fluoro-2-methylphenoxy) -N- {3- [ imino (-/-) ² H ₃ ) Methyl) oxo-lambda ⁶ Thio group]Phenyl } -5- (trifluoromethyl) pyridine-3-carboxamide. ¹ H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.66(dd,J＝2.4,1.0Hz,1H),8.57-8.51(m,1H),8.38(t,J＝1.9Hz,1H),7.98-7.90(m,1H),7.72-7.67(m,1H),7.61(t,J＝7.9Hz,1H),7.27(dd,J＝8.8,5.1Hz,1H),7.20(dd,J＝9.5,3.0Hz,1H),7.11(td,J＝8.5,3.0Hz,1H),4.22(s,1H),2.09(s,3H)。m/z 471.5[M+H] ⁺ (esi+), rt=4.05 LC-MS method 5.

Example 105

According to the Nanion pairWhole cell patch clamp recordings were performed according to standard procedures of (2). The cells were held at a holding potential of-120 mV. A depolarization step of 10mV was applied for 30ms (P1 measurement), followed by a hyperpolarization step to-100 mV for 100ms.An inactivation step of 10 seconds was applied at-40 mV before stepping to-100 mV for 20ms, then stepping to 10mV for 30ms (P2 measurement), and then returning to-100 mV for 30ms. The scan interval was 15 seconds and the sampling rate was 10kHz. After establishment of the whole cell configuration in EC, two wash steps were performed with reference buffer to stabilize the baseline. The compound was then applied to each well by SynchroPatch and the current was recorded in EC for five minutes, followed by the application of tetracaine to obtain complete blocks at the end of the experiment. The efficacy of the compounds was evaluated for two readings (resting state block (P1 measurement) or inactive state block (P2 measurement)) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) control values. The IC50 values are as follows in table 17: "A" means an IC50 of less than or equal to 20nM, "B" means an IC50 of greater than 20nM to less than or equal to 40nM, "C" means an IC50 of greater than 40nM to less than or equal to 200nM, and "D" means an IC50 of greater than 200nM to less than or equal to 500 nM. / >

TABLE 17

Compounds of formula (I)	P1IC50	P2IC50
			1	B	B
2	A	A
			3	A	A

C. Examples of the third group of Compounds

Example 106

A0.25 mm silica gel 60F254 plate (available from EMD MILLIPORE) was used ^TM ) The reaction was monitored by Thin Layer Chromatography (TLC). Purification was performed with CombiFlash NextGen 300 automated flash chromatography system or purified using one of the preparative HPLC methods mentioned below.

Preparation method 1 (P1): early acid process

Preparation method 2 (P2): acid standard method

Preparation method 3 (P3): alkaline early stage method

Preparation method 4 (P4): alkaline standard method

LCMC was collected and analyzed using one of the following methods.

Method 1 (M1): acidic IPC method (METRR 1410-MS17, MS18, MS 19)

Method 2 (M2):

Method 3 (M3): alkaline IPC method (MET-uPLC-AB-2005-MS 16, MSQ 5)

Method 4 (M4): acid final analysis method (METRR-uPLC-AB 101-MSQ1, MSQ2, MSQ 4)

Method 5 (M5): acid final analysis method (METRR 1416-MS18, MS 19)

Method 6 (M6): alkaline final analysis method (MET-uPLC-AB 105-MS16, MSQ 5)

SFC chiral resolution was performed using the following procedure: column: daicel CHIRALPAK IG,250mm×20mm I.D.,5 μm; mobile phase a: CO ₂ /MeOH[0.2％NH ₃ (7M MeOH solution)]=70/30; flow ofDynamic rate: 60g/min;214nm; temperature: 35 DEG C

Example 107

General synthetic scheme

Several methods for preparing the compounds of the present invention are illustrated in the schemes and examples below. The present invention further provides a process for the preparation of a compound of formula I as defined above. In some cases, the order in which the foregoing reaction schemes are carried out may be altered to facilitate the reaction or to avoid undesirable reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

Scheme 1

Scheme 1 shows the use of the amide coupling agents HATU and DIEA as base with R ₂ NH ₂ Treating formic acid A-1 to obtain

General procedure to the a-2 intermediate for the preparation of carboxamide derivatives according to the invention. The A-3 type compound can be prepared by reacting an A-2 type intermediate with various phenols in an organic solvent in a base (e.g., K ₂ CO ₃ 、Cs ₂ CO ₃ DIEA or Et ₃ N) in the presence of a catalyst.

Scheme 2

Alternatively, compounds of formula A-3 can be synthesized in a five-step linear synthesis starting from bischloroformate B-1 by using various substituted phenols in a base (e.g., K ₂ CO ₃ 、Cs ₂ CO ₃ Nucleophilic displacement of Cl adjacent to formate in the presence of NaH, KH or other organic base) to afford the B-2 intermediate. Form B-2 intermediate was further treated with HI (50%), HI (57%) or HI (40%) to give form B-3 intermediate. R is differently substituted ₃ The groups may be introduced by Pd-mediated or Cu-mediated coupling together with a B-3 type intermediate to produce B4. Formic acid of the B-5 intermediate can be prepared by hydrolyzing esters of the B-4 intermediate using a base (e.g., aqueous NaOH, KOH or LiOH). Alternatively, the B-5 form intermediate may be prepared by treating the B-4 form intermediate with 1 to 6N aqueous HCl. The carboxylic acid (B-5) can be activated to acid chloride and is reacted with R ₂ NH ₂ Coupling or carboxylic acid (B-5) can use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to give A-3.

Scheme 3

Alternatively, compounds of formula A-3 may be prepared using various substituted phenols in a base (e.g., K ₂ CO ₃ 、Cs ₂ CO ₃ NaH, KH or other organic base) by nucleophilic displacement of Cl of the C-1 intermediate, to give the C-2 intermediate. Formic acid of the C-3 intermediate can be prepared by hydrolyzing esters of the C-2 intermediate using a base (e.g., aqueous NaOH, KOH, or LiOH). Alternatively, the C-3 form intermediate may be prepared by treating the C-2 form intermediate with 1 to 6N aqueous HCl. The carboxylic acid (C-3) can be activated to acid chloride and is reacted with R ₂ NH ₂ Coupling or carboxylic acid (C-3) can use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to give A-3.

Scheme 4

Alternatively, the A-3 compound may also be prepared by: activating carboxylic acid (A-1) to acid chloride and reacting with R ₂ NH ₂ Coupling or carboxylic acids (A-1) can be carried out using standard amide coupling agents (not limited to TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to obtain D-1. Compounds of type A-3 can be prepared by reacting D-1 intermediates with various phenols in an organic solvent in a base (e.g., naH (60%), K ₂ CO ₃ 、Cs ₂ CO ₃ DIEA or Et ₃ N) in the presence of a catalyst.

Example 108

Specific synthesis

Intermediate 1:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid

Reagents and conditions: a) 4-fluoro-2-methylphenol, K ₂ CO ₃ 、CH ₃ CN,90 ℃ for 16 hours; b) HI,40℃for 5h; c) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, TBAI, cuI, DMF,120 ℃ for 2h; d) LiOH, THF, H ₂ O, room temperature.

Step 1: 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester.

A mixture of 4-fluoro-2-methyl-phenol (3.01 g,23.8 mmol), methyl 3, 6-dichloropyridazine-4-carboxylate (4.70 g,22.7 mmol) and potassium carbonate (4.71 g,34.1 mmol) in acetonitrile (47 mL) was stirred at 80℃for 3h. Cooling the reaction to the chamber Warm, filter, and wash with MeCN (20 mL). The filtrate was concentrated in vacuo to give a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 15% etoac/heptane afforded 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester (95.0%) as a pale yellow oil (4.10 g, 58%). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H). LC-MS (method 5): m/z:297/299[ M+H ]] ⁺ ,(ESI+),RT＝4.26。

Step 2:3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester:

a mixture of 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester (4.10 g,13.1 mmol) in hydroiodic acid (55%) (50 mL, 0.197mol) was stirred at 40℃for 3h. The mixture was left to stand overnight at room temperature. The reaction mixture was filtered. The filter cake was washed with water. The solid was redissolved in 55% aqueous hydrogen iodide (50 mL, 0.197mol) and stirred at 40℃for 24h. The mixture was cooled to room temperature and filtered, the solid was washed with water and dried overnight in a high vacuum oven at 40 ℃ to give 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester (79.0%) as a yellow solid (2.70 g,5.50mmol,42% yield). ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 8.37 (s, 1H), 7.26-7.17 (m, 2H), 7.15-7.05 (m, 1H), 3.91 (s, 3H), 2.09 (s, 3H). LC-MS (method 1): m/z:388.9[ M+H ] ]+,(ESI+),RT＝1.24。

Step 3:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester (80%, 2.70g,5.57 mmol), copper iodide (1.598 g,8.35 mmol), tetrabutylammonium iodide (0.284 g,2.23 mmol) in DMF (10 mL). The mixture was degassed with nitrogen for 5 min and methyl difluoro (fluorosulfonyl) acetate (5.346 g,27.8 mmol) was added and stirred at 90 ℃ for 2h. The reaction was cooled to room temperature, filtered and the filter cake was washed with EtOAc (2×10 mL). The filtrate was washed with brine (50 mL) and over MgSO ₄ Drying, filtration and concentration under reduced pressure gave a crude residue. Purification by silica chromatography eluting with a gradient of 0 to 50% EtOAc in heptane afforded the title compound 3- (4) as a pale yellow solidFluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (0.770 g, 41%). ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 8.54 (s, 1H), 7.32-7.20 (m, 2H), 7.14 (td, j=8.5, 3.2hz, 1H), 3.97 (s, 3H), 2.13 (s, 3H). LC-MS (method 1): m/z:316.95[ M+H ]] ⁺ (esi+), rt=1.06 and unreacted starting material 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester (0.220 g, 13%) as pale yellow oil.

Step 4:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid: to 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (0.460 g,2.31 mmol) in THF: H ₂ Lithium hydroxide (0.288 g,11.5 mmol) was added to the mixture in O (10 mL,4:1; v/v) and the mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solid was filtered, washed with water (2×10 mL), dissolved in EtOAc (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.640 g, 87%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 8.49 (s, 1H), 7.31-7.22 (m, 2H), 7.18-7.09 (m, 1H), 2.12 (s, 3H). LC-MS (method 1): m/z:316.95[ M+H ]] ⁺ ,(ESI+),RT＝1.06。

The intermediates listed in table 18 were prepared by a similar method as described for step 1 of intermediate 1 using the appropriate starting materials.

Table 18.

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The intermediates listed in table 19 were prepared by a similar method as described for step 2 of intermediate 1 using the appropriate starting materials.

Table 19.

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The intermediates listed in table 20 were prepared by a similar method as described for step 3 of intermediate 1 using the appropriate starting materials.

Table 20

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The intermediates listed in table 21 were prepared by a similar method as described for step 4 of intermediate 1 using the appropriate starting materials.

Table 21

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Example 109

Intermediate 70: 2-ethoxy-4-fluoro-phenol

(2-ethoxy-4-fluoro-phenyl) boronic acid (0.725 g,3.94 mmol) was dissolved in THF (15.7 mL) and cooled to 0 ℃. 14.7M hydrogen peroxide (50% in water) (50%, 1.2mL,17.3 mmol) and 2M sodium hydroxide (3.9 mL,7.88 mmol) were then added. The reaction mixture was slowly warmed to room temperature. Stirred at room temperature for 90 minutes. The reaction was diluted with HCl (2N, 20 mL) and water (10 mL) and extracted with EtOAc (. Times.2). The combined organics were dried (Na ₂ SO ₄ ) Filtered and concentrated in vacuo to a dark brown gum. Purification by column chromatography with a gradient of ethyl acetate and heptane (0-50%) gave the title compound 2-ethoxy-4-fluoro-phenol (0.503 g, 69%) as a light brown oil. ¹ H NMR(400MHz,CDCl ₃ ) Delta 6.83 (dd, j=8.7, 5.5hz, 1H), 6.60 (dd, j=9.8, 2.8hz, 1H), 6.55 (td, j=8.6, 2.8hz, 1H), 5.38 (s, 1H), 4.09 (q, j=7.0 hz, 2H), 1.46 (t, j=7.0 hz, 3H). LC-MS (method 3): m/z:155.1[ M-H ]]-,(ESI-),RT＝0.61。

Intermediate 71 and 72

Synthesis of (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate intermediate 71]And (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tertiary butyl (llyl) carbamate (intermediate 72)]。

Reagents and conditions: NH (NH) ₄ (OAc), phI (OAc) 2, etOH, room temperature, 16h; b) t-BuOK, (Boc) ₂ O, t-BuOH, refluxing for 10h; c) Pd (OH) ² 、H ₂ MeOH, room temperature, 2h; d) SFC purification

Step 1: imino (methyl) (3-nitrophenyl) -lambda ⁶ Thioketone.

To a mixture of (3-nitrophenyl) sulfane (8.2 g,48.5 mmol) and ammonium acetate (5.6 g,72.7 mmol) in EtOH (120 mL) was added PhI (OAc) in one portion ₂ (31.2 g,97 mmol). The reaction mixture was stirred at room temperature under atmospheric air for 16h. The mixture was concentrated directly to give a residue which was purified by silica gel chromatography column (PE: ea=5:1 to 1:3) to give imino (methyl) (3-nitrophenyl) - λ as a white solid ⁶ Thioketone (7.0 g, 72%). MS (esi+): m/z Experimental value 201.03[ M+H ]] ⁺ 。

Step 2: (methyl (3-nitrophenyl) (oxo) -lambda ⁶ -a sulfoanyl) carbamic acid tert-butyl ester.

At N ₂ To imino (methyl) (3-nitrophenyl) -16-thione (3.5 g,17.5 mmol) under protectionTo a solution of t-BuOH (200 mL) in ice-water cooled t-BuOK (3.9 g,35.0 mmol) was added. Subsequently, slow addition (Boc) ₂ O (7.6 g,35.0 mmol) and then the reaction mixture was refluxed for 10h. The reaction mixture was saturated with NH ₄ The Cl solution (200 mL) was quenched and extracted with EA (200 mL. Times.2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Drying and concentration gave a residue which was purified by silica gel chromatography column (PE: ea=5:1 to 1:1) to give (methyl (3-nitrophenyl) (oxo) - λ as a yellow solid ⁶ Tert-butyl (sulfoalkyl) carbamate (1.8 g, 34%). LC-MS (esi+): m/z301.09[ M+H ]] ⁺ 。

Step 3: (3-aminophenyl) (imino) (methyl) -lambda ⁶ Thioketone.

To (methyl (3-nitrophenyl) (oxo) -lambda ⁶ To a solution of tert-butyl (sulfoalkyl) carbamate (1.8 g,6 mmol) in MeOH (30 mL) was added Pd (OH) ₂ (300 mg) and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue, which was redissolved in EA (30 mL) and the resulting solution was filtered again through celite and washed with EA (100 mL). The filtrate was concentrated to give ((3-aminophenyl) (methyl) (oxo) -lambda as an off-white solid ⁶ Tert-butyl (alkylene) carbamate (1.4 g, 86%). MS (esi+): experimental value of m/z 271.10[ M+H ]] ⁺ 。

Step 4: SFC separation.

The racemic product was separated using chiral high performance liquid chromatography, wherein chiral separation conditions: column: daicel CHIRALPAK IG,250mm×20mm I.D.,5 μm; mobile phase a: CO ₂ /MeOH[0.2％NH ₃ (7M MeOH solution) ]=70/30; flow rate: 60g/min;214nm; temperature: 35 ℃. The first eluting isomer (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate intermediate 71]。 ¹ H NMR(DMSO-d ₆ ) Delta 7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s.9H), and the second eluting isomer (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tertiary butyl (llyl) carbamate (intermediate 72)]。 ¹ H NMR(DMSO-d ₆ )δ7.26(t,1H),7.08(s,1H),6.97(d,1H),6.83(d,1H),5.71(s,2H),3.28(s,3H),1.27(s.9H)。

Example 110

Compound 1:3- (4-fluoro-2-methoxyphenoxy) -N- (2- (methylsulfonyl) pyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide.

Reagents and conditions: 2- (methylsulfonyl) pyridin-4-amine, 50% propylphosphonic acid anhydride in EtOAc solution, DIEA, DMAP, DCM, room temperature.

A mixture of 50% propylphosphonic anhydride solution/EtOAc (0.098 g,0.309 mmol), 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.090 g,0.257 mmol), N-dimethylpyridin-4-amine (6.3 mg,0.0515 mmol) and N-ethyl-N-isopropyl-propan-2-amine (DIEA) (0.090 mL,0.515 mmol) was dissolved in DCM (1.28 mL) under nitrogen at room temperature. After 15 minutes 2- (methylsulfonyl) pyridin-4-amine (0.053 g,0.309 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was poured into water (10 mL) and brine (5 mL) and extracted with DCM (3×10 mL), over Na ₂ SO ₄ Dried and concentrated. Purification by method 2 gave the title compound 3- (4-fluoro-2-methoxy-phenoxy) -N- (2-methylsulfonyl-4-pyridinyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.087 g, 69%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.67 (s, 1H), 8.74 (d, j=5.4 hz, 1H), 8.68 (s, 1H), 8.40 (d, j=1.9 hz, 1H), 7.91 (dd, j=5.4, 2.0hz, 1H), 7.39 (dd, j=8.8, 5.8hz, 1H), 7.16 (dd, j=10.7, 2.9hz, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 3.73 (s, 3H), 3.29 (s, 3H). LC-MS (method 1): m/z:487.3[ M+H ]] ⁺ ,(ESI+),RT＝3.15。

The compounds listed in table 22 were synthesized by a similar method as described for compound 1 using the appropriate acid and substituted aniline.

Table 22

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Example 111

Compound 59:3- (4-fluoro-2-methyl-phenoxy) -N-pyridazin-4-yl-6- (trifluoromethyl) pyridazin-4-carboxamide

Reagents and conditions: pyridazin-4-amine, HATU, DIEA, DMF,25 ℃,1h;

n- [ (dimethylamino) 3H- [1,2,3 ] was purified under nitrogen at room temperature]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]A mixture of-N-methyl ammonium hexafluorophosphate (0.216 g,0.569 mmol) and 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.150 g,0.474 mmol) was dissolved in DMF (1.9 mL). Along with itAfter the last addition of pyridazin-4-amine (0.054 g,0.569 mmol) then N-ethyl-N-isopropyl-propan-2-amine (0.17 mL,0.949 mmol) was added. The reaction mixture was stirred at room temperature for 1h. The reaction was diluted with brine (20 mL) and extracted with EtOAc (2×10 mL), the organic layer was separated, dried (Na ₂ SO ₄ ) Filtered and concentrated in vacuo to give a crude residue. Purification by preparative HPLC using method a gave the title compound 3- (4-fluoro-2-methyl-phenoxy) -N-pyridazin-4-yl-6- (trifluoromethyl) pyridazin-4-carboxamide (0.139 g, 75%) as an off-white solid. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.53 (s, 1H), 9.42-9.32 (m, 1H), 9.22-9.12 (m, 1H), 8.70 (s, 1H), 8.05 (dd, j=6.0, 2.7hz, 1H), 7.35 (dd, j=9.0, 5.0hz, 1H), 7.26 (dd, j=9.4, 3.0hz, 1H), 7.16 (td, j=8.6, 3.2hz, 1H), 2.13 (s, 3H). LC-MS (method 4): m/z 394.2[ M+H ]] ⁺ ,(ESI+),RT＝2.93

Compound 60:3- (3- (2, 4-difluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridine 1-oxide.

Reagents and conditions: 3-aminopyridine 1-oxide, HATU, DIEA, DMF,25 ℃ for 16h;

to a solution of 3- (2, 4-difluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.110 g,0.34mmol,1.0 eq.), 3-aminopyridine 1-oxide (0.075 g,0.68mmol,2.0 eq.) and DIEA (0.222 g,1.72mmol,5.0 eq.) in DMF (10 mL) was added HATU (0.196 g,0.52mmol,1.5 eq.). The reaction mixture was stirred at 25℃for 16h. After the reaction, H is used ₂ The mixture was quenched with O (40 mL) and extracted with EtOAc (3×50 mL), and the organic layer was concentrated and the residue purified by preparative HPLC to give 3- (3- (2, 4-difluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) pyridine-1-oxide (0.0405 g, 28%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.30(s,1H),8.73(d,J＝4.2Hz,2H),8.09(d,J＝6.2Hz,1H),7.70-7.40(m,4H),7.25(t,J＝8.5Hz,1H)。MS(ESI+)：m/z 413.1[M+H] ⁺ 。

Compounds 61 to 88 listed in table 23 were synthesized by a similar method as described for compound 60 using the appropriate carboxylic acid and substituted aryl or heteroaryl aniline.

Table 23

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Example 112

Compound 89:3- (2-chloro-4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Iodotrimethylsilane, CH ₃ CN，60℃，24h

To a solution of 3- (2-chloro-4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.117 g,0.264 mmol) in anhydrous acetonitrile (10 mL) was added iodotrimethylsilane (0.062 mL) at room temperature. After the completion of the iodotrimethylsilane addition, the mixture was stirred at 60 ℃ for 24h. At the end of this period, the mixture was cooled to room temperature and the solvent was evaporated to dryness, water (15 mL) was added and extracted with EtOAc (3×20 mL). The EtOAc layers were combined and washed with water (20 mL) and brine (20 mL), and the organic layer was dried (Na ₂ SO ₄ ) Filtered, and the solvent evaporated. SiO of the mixture in a gradient with 0 to 15% EtOAc/DCM ₂ Chromatography thereon gave 3- (2-chloro-4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.0416 g, 37%). ¹ H NMR(300MHz,DMSO-d ₆ ) δ11.40 (s, 1H), 10.95 (s, 1H), 8.72 (s, 1H), 7.71 (dd, j=8.4, 3.0hz, 1H), 7.63 (dd, j=9.1, 5.2hz, 1H), 7.47-7.34 (m, 2H), 6.78 (d, j=2.0 hz, 1H), 6.38 (dd, j=7.2, 2.1hz, 1H). LC-MS (method 2): m/z 427.0[ M-H ]] ⁺ 。

Compound 90:3- (4-fluoro-2-methylphenoxy) -N- (5-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 89 using 3- (4-fluoro-2-methylphenoxy) -N- (2-methoxy-5-methylpyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.31 (s, 1H), 9.95 (s, 1H), 8.63 (s, 1H), 7.36 (dd, j=8.9, 4.9hz, 1H), 7.27 (dd, j=9.5, 3.1hz, 1H), 7.24 (s, 1H), 7.17 (td, j=8.6, 3.2hz, 1H), 7.11 (s, 1H), 2.15 (s, 3H), 2.00 (s, 3H). LC-MS (method 5): m/z 422.9[ M+H ]] ⁺ ,(ESI+),RT＝3.83。

Compound 91:3- (4-fluoro-2-methylphenoxy) -N- (3-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 89 using 3- (4-fluoro-2-methylphenoxy) -N- (2-methoxy-3-methylpyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.47 (s, 1H), 10.26 (s, 1H), 8.63 (s, 1H), 7.35 (dd, j=8.6, 5.3hz, 1H), 7.30-7.23 (m, 2H), 7.16 (td, j=8.6, 3.1hz, 1H), 6.76 (d, j=7.1 hz, 1H), 2.14 (s, 3H), 1.95 (s, 3H). LC-MS (method 6): m/z 423.2[ M+H ] ] ⁺ ,(ESI+),RT＝3.05。

Compound 92:3- (4-fluoro-2-methylphenoxy) -N- (2-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 89 using 3- (4-fluoro-2-methylphenoxy) -N- (6-methoxy-2-methylpyridin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.73 (s, 1H), 10.10 (s, 1H), 8.61 (s, 1H), 7.43 (d, j=9.5 hz, 1H), 7.33 (dd, j=9.0, 5.1hz, 1H), 7.26 (dd, j=9.5, 3.0hz, 1H), 7.16 (td, j=8.5, 3.2hz, 1H), 6.22 (d, j=8.9 hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H). LC-MS (method 6): m/z 423.2[ M+H ]] ⁺ ,(ESI+),RT＝2.85。

Compound 93:3- (4-fluoro-2-methyl-phenoxy) -6-methyl-N- [3- (methylsulfonyl) phenyl ] pyridazine-4-carboxamide

Reagents and conditions: a) HATU, DCM, DIEA, room temperature, 18h; b) 4-fluoro-2-methyl-phenol, cs ₂ CO ₃ 、CH ₃ CN, room temperature, 16h; c) Diacetoxyiodo-benzene, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 3h.

Step 1: 6-methyl-N- (3-methylsulfonylphenyl) -3- (triazolo [4, 5-b)]Pyridin-3-yloxy) pyridazine-4-carboxamide. A mixture of 3- (methylthio) aniline (1.2 mL,6.95 mmol), 3-chloro-6-methylpyridazine-4-carboxylic acid (1.00 g,5.79 mmol) was dissolved in DCM (23.179 mL) at room temperature under nitrogen. Subsequently N- [ (dimethylamino) (3H- [1,2, 3) is added in one portion ]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-N-methyl ammonium Hexafluorophosphate (HATU) (2.42 g,6.37 mmol). N-ethyl-N-isopropyl-propan-2-amine (2.0 mL,11.6 mmol) was added dropwise to the above mixture for 2-3 min. The reaction mixture was stirred at room temperature for 18h. Saturated NaHCO used for reaction ₃ The solution (30 mL) was diluted and stirred vigorously for 45 minutes, then extracted with DCM (30 mL. Times.2). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give a dark brown crude residue. Purification by chromatography with a gradient elution of 0 to 50% etoac/heptane afforded the isolated impure title compound 6-methyl-N- (3-methylsulfonylphenyl) -3- (triazolo [4, 5-b) as a beige solid]Pyridin-3-yloxy) pyridazine-4-carboxamide (68.0%) (1.29 g,2.23mmol,39% yield). ¹ H NMR(500MHz,CDCl ₃ ) δ9.51 (s, 1H), 8.72 (dd, j=4.5, 1.4hz, 1H), 8.53 (dd, j=8.4, 1.4hz, 1H), 8.10 (s, 1H), 7.71 (t, j=1.9 hz, 1H), 7.51 (dd, j=8.4, 4.5hz, 1H), 7.46 (ddd, j=8.1, 2.0,0.8hz, 1H), 7.30 (t, j=8.0 hz, 1H), 7.10 (ddd, j=7.9, 1.8,0.9hz, 1H), 2.76 (s, 3H), 2.51 (s, 3H). LC-MS (method 3): m/z 394.4[ M+H ]] ⁺ ,(ESI+),RT＝0.76。

Step 2:3- (4-fluoro-2-methyl-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide. 6-methyl-N- (3-methylsulfonylphenyl) -3- (triazolo [4, 5-b) under nitrogen ]Pyridine-3-yloxy) pyridazine-4-carboxamide (68%, 0.25g,0.432 mmol) and 4-fluoro-2-methyl-phenol (65 mg, 0.399 mmol) were suspended in anhydrous acetonitrile (4.3211 mL) and treated with cesium carbonate (0.282 g,0.864 mmol). The resulting mixture was stirred at room temperatureOvernight. Saturated NH for reactant ₄ Cl solution (10 mL) and EtOAc (10 mL) were diluted and then stirred at room temperature for 10 min. The layers were shaken and separated, then re-extracted with EtOAc in water (×1). The combined organics were dried (Na ₂ SO ₄ ) Filtered and concentrated in vacuo to give a brown gum. The material was purified by column chromatography with a gradient of EtOAc and heptane (0-100%) to give the title compound 3- (4-fluoro-2-methyl-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (0.122 g, 71%) as a tan solid. ¹ H NMR(400MHz,CDCl ₃ ) δ9.75 (s, 1H), 8.21 (s, 1H), 7.71 (t, j=1.8 hz, 1H), 7.36 (m, 1H), 7.29 (t, j=7.9 hz, 1H), 7.17 (dd, j=8.8, 4.8hz, 1H), 7.09 (dt, j=7.7, 1.1hz, 2H), 7.05 (dd, j=8.9, 2.9hz, 1H), 7.00 (td, j=8.3, 3.1hz, 1H), 2.75 (s, 3H), 2.52 (s, 3H), 2.22 (s, 3H). LC-MS (method 3): m/z 384[ M+H ]] ⁺ ,(ESI+),RT＝0.89。

Step 3:3- (4-fluoro-2-methyl-phenoxy) -6-methyl-N- [3 (methylsulfonyl) phenyl]Pyridazine-4-carboxamide. 3- (4-fluoro-2-methyl-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (0.122 g,0.318 mmol) was dissolved in methanol (3.2 mL) and treated with ammonium carbonate (0.046 g,0.477 mmol) and diacetoxyiodo-benzene (0.236 g,0.732 mmol), each added in one portion. After 60 minutes, more ammonium carbonate (0.046 g,0.477 mmol) and diacetoxyiodo-benzene (0.236 g,0.732 mmol) were added. After 2 hours at room temperature the mixture was concentrated in vacuo to give a brown gum. Purification using column chromatography with a gradient of methanol/ethyl acetate yielded the impure title compound. This material was further purified using preparative HPLC (Gilson 6) to give the title compound (0.064 mg, 47%). ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.06 (s, 1H), 8.36 (t, j=1.9 hz, 1H), 7.90 (ddd, j=8.0, 2.0,0.9hz, 1H), 7.90 (s, 1H), 7.70 (ddd, j=7.8, 1.6,1.1hz, 1H), 7.62 (t, j=7.9 hz, 1H), 7.25 (dd, j=8.9, 5.1hz, 1H), 7.20 (dd, j=9.4, 3.0hz, 1H), 7.11 (td, j=8.5, 3.2hz, 1H), 4.24 (s, 1H), 3.07-3.05 (m, 3H), 2.61 (s, 3H), 2.10 (s, 3H). LC-MS (method 6): m/z 415.3[ M+H ]]+,(ESI+),RT＝2.55。

Compound 94:3- (4-fluoro-2-methoxyphenoxy) -6-methyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide

Reagents and conditions: a) 4-fluoro-2-methoxyphenol, cs ₂ CO ₃ Acetonitrile, room temperature, 16h; b) Diacetoxyiodo-benzene, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 3h.

Step 1-3- (4-fluoro-2-methoxyphenoxy) -6-methyl-N- (3- (methylthio) phenyl) pyridazine-4-carboxamide. 6-methyl-N- (3-methylsulfonylphenyl) -3- (triazolo [4, 5-b)]Pyridine-3-yloxy) pyridazine-4-carboxamide (68%, 0.500g,0.864 mmol) and 4-fluoro-2-methoxyphenol (0.150 g,1.04 mmol) and cesium carbonate (0.563 g,1.73 mmol) were suspended in anhydrous acetonitrile (8.6 mL) and the resulting mixture was stirred at room temperature for 16h. The reaction was treated with saturated NH ₄ Cl solution (20 mL) and DCM (10 mL) were diluted and then stirred at room temperature for 10 min. The layers were separated and the aqueous solution re-extracted with DCM (10 mL). The combined organics were concentrated in vacuo to give a brown solid which was purified by column chromatography with a gradient of ethyl acetate and heptane (0-100%) to give the title compound as a pink crystalline solid (0.320 g 88%). ¹ H NMR(500MHz,CDCl ₃ ) Delta 9.84 (s, 1H), 8.18 (s, 1H), 7.71 (t, J=1.9 Hz, 1H), 7.42 (dd, J=8.6, 5.4Hz, 1H), 7.38 (ddd, J=8.1, 2.0,0.9Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.08 (ddd, J=7.8, 1.8,1.0Hz, 1H), 6.79 (dt, J=4.6, 2.2Hz, 1H), 6.78-6.74 (m, 1H), 3.79 (s, 3H), 2.78 (s, 3H), 2.52 (s, 3H). LC-MS (method 6): m/z 400.5[ M+H ]] ⁺ ,(ESI+),RT＝4.01。

Step 2-3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound was prepared by a procedure similar to that described for step 3 of compound 93 using 3- (4-fluoro-2-methoxyphenoxy) -6-methyl-N- (3- (methylthio) phenyl) pyridazine-4-carboxamide. ¹ H NMR(500MHz,DMSO-d ₆ )δ11.00(s,1H),8.37(t,J＝1.8Hz,1H),7.94-7.89(m,1H),7.86(s,1H),7.73-7.67(m,1H),7.61(t,J＝7.9Hz,1H),7.31(dd,J＝8.8,5.9Hz,1H),7.10(dd,J＝10.7,2.9Hz,1H),6.84(td,J＝8.5,2.9Hz1H), 4.24 (s, 1H), 3.70 (s, 3H), 3.06 (s, 3H), 2.61 (s, 3H). LC-MS (method 6): m/z 431.3[ M+H ]]+,(ESI+),RT＝2.43。

Compound 95:3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (S-methylsulfonyl) phenyl) pyridazine-4-carboxamide

Step 1-3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (methylthio) phenyl) pyridazine-4-carboxamide. The title compound (0.3838 g, 99%) as an off-white crystalline solid was obtained by a similar method as described for step 2 of compound 93, but using 2-ethoxy-4-fluoro-phenol and 6-methyl-N- (3-methylsulfonylphenyl) -3- (triazolo [4,5-b ] ]Pyridin-3-yloxy) pyridazine-4-carboxamide. ¹ H NMR(500MHz,CDCl ₃ ) Delta 9.83 (s, 1H), 8.16 (s, 1H), 7.72 (t, J=1.9 Hz, 1H), 7.39 (dd, J=9.4, 5.7Hz, 1H), 7.37-7.34 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.08 (ddd, J=7.8, 1.8,1.0Hz, 1H), 6.79-6.76 (m, 1H), 6.75 (d, J=2.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 2.77 (s, 3H), 2.51 (s, 3H), 1.15 (t, J=7.0 Hz, 3H). LC-MS (method 1): m/z 414.3[ M+H ]] ⁺ ,(ESI+),RT＝0.90。

Step 2-3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (S-methanesulfonyl) phenyl) pyridazine-4-carboxamide. The title compound was prepared by a procedure similar to that described for step 3 of compound 93 using 3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (methylthio) phenyl) pyridazine-4-carboxamide. ¹ H NMR(500MHz,DMSO-d ₆ ) δ10.97 (s, 1H), 8.37 (t, j=1.8 hz, 1H), 7.96-7.88 (m, 1H), 7.87 (s, 1H), 7.71-7.68 (m, 1H), 7.61 (t, j=7.9 hz, 1H), 7.32 (dd, j=8.8, 5.9hz, 1H), 7.06 (dd, j=10.7, 2.9hz, 1H), 6.82 (td, j=8.5, 2.9hz, 1H), 4.24 (s, 1H), 3.97 (q, j=7.0 hz, 2H), 3.06 (s, 3H), 2.61 (s, 3H), 1.05 (t, j=7.0 hz, 3H). LC-MS (method 6): m/z 445.3[M+H] ⁺ ,(ESI+),RT＝2.62。

Compound 96:3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 3- (methylthio) aniline, HATU, DMF, DIEA, room temperature, 18h; b) Diacetoxyiodo-benzene, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 3h.

Step 1:3- (2-chloro-4-fluorophenoxy) -N- [3- (methylsulfanyl) phenyl]-6- (trifluoromethyl) pyridazine-4-carboxamide. To a mixture of 3- (2-chloro-4-fluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.100 g, 0.293 mmol), 3- (methylthio) aniline (0.041 g,0.356 mmol), HATU (0.226 g,0.594 mmol) in DMF (3 mL) was added DIEA (0.129 mL,0.743 mmol) at 25 ℃ and stirring was continued for 2 hours. At the end of this period, water (5 mL) was added and extracted with EtOAc (3X 25 mL). The organics were laminated and washed with 1M LiCl solution (20 mL) followed by brine (20 mL). The EtOAc layer was dried (Na ₂ SO ₄ ) Filtered, and the solvent evaporated. The crude mixture was purified on SiO with a gradient of 0 to 60% EtOAc in hexane ₂ Chromatography on the above to give 3- (2-chloro-4-fluorophenoxy) -N- [3- (methylsulfanyl) phenyl]-6- (trifluoromethyl) pyridazine-4-carboxamide (0.086 g, 63.23%). ¹ H NMR(300MHz,DMSO-d ₆ ) Delta 10.90 (s, 1H), 8.70 (s, 1H), 7.79-7.54 (m, 3H), 7.49-7.22 (m, 3H), 7.07 (ddd, j=7.8, 1.9,1.1hz, 1H), 2.48 (s, 3H). LC-MS (method 2): m/z 456.3[ M-H ]] ⁺ 。

Step 2:3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. 3- (2-chloro-4-fluorophenoxy) -N- [3- (methylsulfanyl) phenyl ]-6- (trifluoromethyl) pyridazine-4-carboxamide 0.133g, 0.2918 mmol) was dissolved in methanol (5.0 mL) and treated with ammonium carbonate (0.42 g, 0.433 mmol) and diacetoxyiodo-benzene (0.215 mg,0.668 mmol), each added in one portion. The reaction mixture was stirred at room temperature for 3h. At the end of this period the reaction is mixedThe mixture was concentrated in vacuo and the crude mixture was taken up in a gradient of SiO with 0 to 100% EtOAc/DCM ₂ Chromatography was performed thereon to give 3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.098 g, 69%). ¹ H NMR(300MHz,DMSO-d ₆ ) δ11.21 (s, 1H), 8.73 (s, 1H), 8.35 (t, j=1.9 hz, 1H), 7.99-7.87 (m, 1H), 7.79-7.58 (m, 4H), 7.41 (ddd, j=9.1, 8.1,3.0hz, 1H), 4.27 (s, 1H), 3.07 (d, j=1.1 hz, 3H). LC-MS (method 2): m/z 489.5[ M+H ]] ⁺ 。

Compound 97:3- (2-chloro-4-fluorophenoxy) -N- (2- (S-methanesulfonyl) pyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 2- (methylthio) pyridin-4-amine, HATU, DMF, DIEA, room temperature, 18h; b) Diacetoxyiodo-benzene, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 3h.

Step 1:3- (2-chloro-4-fluorophenoxy) -N- (2- (methylthio) pyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound (0.0913 g, 45%) was prepared by a procedure similar to that described for step 1 of compound 96 using 3- (2-chloro-4-fluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid and 2- (methylthio) pyridin-4-amine. ¹ H NMR(300MHz,CDCl ₃ )δ9.49(s,1H),8.66(s,1H),8.42(dd,J＝5.6,0.7Hz,1H),7.63(dd,J＝2.1,0.7Hz,1H),7.47(dd,J＝9.1,4.9Hz,1H),7.36(dd,J＝7.7,2.9Hz,1H),7.31-7.15(m,3H),2.59(s,3H)。

Step 2:3- (2-chloro-4-fluorophenoxy) -N- (2- (S-methanesulfonyl) pyridin-4-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound (0.0366 g, 42%) was prepared by a procedure similar to that described for step 2 of compound 96. ¹ H NMR(300MHz,DMSO-d ₆ ) δ11.62 (s, 1H), 8.77 (s, 1H), 8.69 (d, j=5.4 hz, 1H), 8.40 (d, j=2.0 hz, 1H), 7.86 (dd, j=5.4, 2.1hz, 1H), 7.76-7.58 (m, 2H), 7.41 (ddd, j=9.1, 8.1,3.0hz, 1H), 4.44 (s, 1H), 3.16 (d, j=1.1 hz, 3H). LC-MS (method 2): m/z 490.4[ M+H ]] ⁺ 。

Compound 98:3- (4-fluoro-2-methylphenoxy) -N- (4- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound 3- (4-fluoro-2-methylphenoxy) -N- (4- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide was prepared by a similar procedure to that described for step 2 of compound 96 using 3- (4-fluoro-2-methylphenoxy) -N- (4- (methylsulfanyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.21 (s, 1H), 8.67 (s, 1H), 7.99-7.85 (m, 4H), 7.35 (dd, j=8.9, 5.1hz, 1H), 7.25 (dd, j=9.4, 2.9hz, 1H), 7.15 (td, j=8.6, 3.2hz, 1H), 4.17 (s, 1H), 3.08-3.00 (m, 3H), 2.13 (s, 3H). LC-MS (method 5): m/z 469.1[ M+H ]]+,(ESI+),RT＝3.80。

Compound 99:3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: 3- (methylthio) aniline, propylphosphonic anhydride (50%/EtOAc), DMAP, DIEA, DCM, room temperature, 3h; b) Diacetoxyiodo-benzene, (NH) ₄ ) ₂ CO ₃ MeOH, room temperature, 3h.

Step 1:3- (4-fluoro-2-methoxyphenoxy) -N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound was prepared by a procedure similar to that described for compound 1 using 3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid and 3- (methylthio) aniline. ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 10.85 (s, 1H), 8.60 (s, 1H), 7.67 (t, j=1.9 hz, 1H), 7.49-7.40 (m, 1H), 7.40-7.28 (m, 2H), 7.15 (dd, j=10.7, 2.8hz, 1H), 7.10-6.99 (m, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 3.73 (s, 3H), 2.48 (s, 3H). LC-MS (method 1) m/z 453.9[ M+H ]]+,(ESI+),RT＝4.87。

Step 2:3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound was prepared by a procedure similar to that described for step 2 of compound 93 using 3- (4-fluoro-2-methoxyphenoxy) -N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide, (NH) ₄ ) ₂ CO ₃ And diacetoxyiodo-benzene to give 3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide as a racemic mixture. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.20 (s, 1H), 8.63 (s, 1H), 8.38-8.32 (m, 1H), 7.96-7.88 (m, 1H), 7.77-7.69 (m, 1H), 7.64 (t, j=7.9 hz, 1H), 7.38 (dd, j=8.8, 5.8hz, 1H), 7.15 (dd, j=10.7, 2.9hz, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 4.27 (s, 1H), 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (method 1): m/z 485.0[ M+H ]]+,(ESI+),RT＝3.84。

Compounds 100 and 101: first eluting isomer and second eluting isomer

The racemic mixture from compound 99 was purified by SFC to give the title compound: first eluting isomer (Compound 100) ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.18 (s, 1H), 8.63 (s, 1H), 8.35 (t, j=1.8 hz, 1H), 7.95-7.90 (m, 1H), 7.72 (dt, j=7.8, 1.1hz, 1H), 7.64 (t, j=7.9 hz, 1H), 7.38 (dd, j=8.8, 5.8hz, 1H), 7.16 (dd, j=10.7, 2.9hz, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 4.26 (s, 1H), 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (method 6): m/z 485.3[ M+H ]] ⁺ (esi+), rt=3.09 and the second eluting isomer (compound 101) - ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.20 (s, 1H), 8.61 (s, 1H), 8.34 (t, j=1.9 hz, 1H), 7.94-7.89 (m, 1H), 7.74-7.69 (m, 1H), 7.63 (t, j=7.9 hz, 1H), 7.37 (dd, j=8.8, 5.8hz, 1H), 7.15 (dd, j=10.7, 2.9hz, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 4.25 (s, 1H), 3.73 (s, 3H), 3.06 (s, 3H). LC-MS (method 1): m/z 484.9[ M+H ]] ⁺ ,(ESI+),RT＝3.83。

Compound 102: (R) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) (R) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tertiary butyl (llyl) carbamate (intermediate 72)]HATU, DIEA, DMF, room temperature, 1h; b) 4M HCl/dioxane, DCM, room temperature, 2h.

Step 1: (R) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ -t-butyl sulfinyl) carbamate: 3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (300 mg,0.95 mmol) was purified under nitrogen at 25℃to give (R) - ((3-aminophenyl) (methyl) (oxo) - λ) ⁶ Tertiary butyl (llyl) carbamate (intermediate 72)]To a mixture of (255 mg,0.94 mmol) and N, N-diisopropylethylamine (365 mg,2.8 mmol) in DMF (5 mL) was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uranium (719 mg,1.8 mmol). The reaction mixture was stirred at 25℃for 1h. The reaction mixture was quenched with ice water and extracted with EA. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Drying and concentration gave the crude product. The residue was purified on SiO with a gradient of 0 to 60% EtOAc/petroleum ether ₂ Chromatography thereon gave (R) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) - λ as a yellow oil ⁶ Tert-butyl (510 mg, 94%) carbamate. LC-MS: m/z 591.0[ M+23 ]] ⁺ 。

Step 2: (R) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. (R) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda at 25 ℃C ⁶ To a mixture of tert-butyl (alkylene) carbamate (0.510 g,0.89 mmol) in DCM (3 mL) was added HCl/1, 4-dioxane (4M, 3 mL). The reaction mixture was stirred at 25℃for 2h. Concentrating the reaction mixtureThe crude product was obtained. The residue was purified by reverse phase flash chromatography (with ACN/H ₂ O(0.1％NH ₃ ) Purification by 0 to 45% elution) afforded (R) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.300 g, 71%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.20(s,1H),8.67(s,1H),8.35(t,J＝4Hz,1H),7.98-7.87(m,1H),7.73(dt,J＝8Hz,1.2Hz,1H),7.65(t,J＝8Hz),7.35(dd,J＝8Hz,4Hz,1H),7.26(dd,J＝8Hz,3.2Hz,1H),7.16(td,J＝8.4Hz,3.2Hz,1H),4.27(s,1H),3.11-3.02(s,3H),2.13(s,3H)。LC-MS(ESI)：m/z469.1[M+1] ⁺ 。

Compound 103: (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) (S) - ((3-aminophenyl) (methyl) (oxo) -lambda ⁶ Tert-butyl (sulfoalkylene) carbamate intermediate 71]HATU, DIEA, DMF, room temperature, 1h; b) 4M HCl/dioxane, DCM, room temperature, 2h.

Step 1: (S) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda ⁶ -a sulfoanyl) carbamic acid tert-butyl ester. 3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.350 g,1.1 mmol), (S) - ((3-aminophenyl) (methyl) (oxo) - λ) at 25℃under nitrogen atmosphere ⁶ To a mixture of tert-butyl (sulfinyl) carbamate (0.298 g,1.1 mmol) and N, N-diisopropylethylamine (0.428 g,3.3 mmol) in DMF (5 mL) was added HATU (0.839 g,2.2 mmol). The reaction mixture was stirred at 25℃for 1h. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Drying and concentration gave the crude product, which was purified by flash chromatography (eluting with 0 to 60% EA/PE) to give (S) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) as a yellow oil) (oxo) -lambda ⁶ Tert-butyl (sulfinyl) carbamate (0.550 g, 87%). LC-MS: m/z Experimental value 591.0[ M+23 ]] ⁺ 。

Step 2: (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. (S) - ((3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -lambda at 25 ℃C ⁶ To a mixture of tert-butyl (alkylene) carbamate (0.550 g,0.96 mmol) in DCM (3 mL) was added HCl/1, 4-dioxane (4M, 3 mL). The reaction mixture was stirred at 25℃for 2h. The reaction mixture was concentrated to give a crude product. The residue was purified by reverse phase flash chromatography (with ACN/H ₂ O(0.1％NH ₃ ) From 0 to 45% elution) to give (S) -3- (4-fluoro-2-methylphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.305 g, 67%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.20 (s, 1H), 8.67 (s, 1H), 8.35 (t, j=4 Hz, 1H), 7.98-7.87 (m, 1H), 7.73 (dt, j=8 Hz,1.2Hz, 1H), 7.65 (t, j=8 Hz), 7.35 (dd, j=8 Hz,4Hz, 1H), 7.26 (dd, j=8 Hz,3.2Hz, 1H), 7.16 (td, j=8.4 Hz,3.2Hz, 1H), 4.27 (s, 1H), 3.11-3.02 (s, 3H), 2.13 (s, 3H). LC-MS: m/z Experimental value 469.1[ M+1 ]] ⁺ 。

Compounds 104 and 105:3- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide and 3- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfinylphenyl) pyridazine-4-carboxamide

Reagents and conditions: potassium hydrogen persulfate, meOH, room temperature, 16h

A solution of 3- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (0.130 g,0.325 mmol) in methanol (3.25 mL) was treated with potassium hydrogen persulfate (0.109 g,0.716 mmol). The resulting mixture was stirred at room temperature overnight. Additional potassium hydrogen persulfate (0.109 g,0.716 mmol) was then added and the mixture was stirred at room temperature for an additional 6 hours When (1). The reaction mixture was washed with DCM (25 mL) and saturated NaHCO ₃ The solution (25 mL) was diluted. The layers were separated and the aqueous solution re-extracted with DCM (25 mL). The combined organics were concentrated in vacuo to a pale yellow solid. This material was purified using preparative HPLC method 1 to give 3- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridazine-4-carboxamide (0.087 g, 61%) as a white solid, ¹ H NMR(500MHz,CDCl ₃ ) δ10.10 (s, 1H), 8.18-8.12 (m, 3H), 7.76 (dt, j=7.7, 1.3hz, 1H), 7.66-7.57 (m, 1H), 7.47 (dd, j=8.7, 5.6hz, 1H), 6.84-6.74 (m, 2H), 3.82 (s, 3H), 3.09 (s, 3H), 2.76 (s, 3H). LC-MS (method 6): m/z 432.3[ M+H ]]+, (esi+), rt=2.78, and the second title compound 3- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfinylphenyl) pyridazine-4-carboxamide (0.015 g, 10%) as an off-white solid. ¹ H NMR(500MHz,DMSO-d ₆ ) δ10.96 (s, 1H), 8.13 (t, j=1.7 hz, 1H), 7.86 (s, 1H), 7.81-7.76 (m, 1H), 7.57 (t, j=7.9 hz, 1H), 7.42 (m, 1H), 7.31 (dd, j=8.8, 5.9hz, 1H), 7.09 (dd, j=10.7, 2.9hz, 1H), 6.84 (td, j=8.5, 2.9hz, 1H), 3.70 (s, 3H), 2.75 (s, 3H), 2.60 (s, 3H). LC-MS (method 1): m/z 416.0[ M+H ]]+,(ESI+),RT＝3.45。

Compound 106:3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

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Reagents and conditions: a) 4-methyl-3- (methylthio) aniline, propylphosphonic anhydride (50%/EtOAc), DMAP, DIEA, DCM, room temperature, 3h; b) Potassium hydrogen persulfate, meOH, room temperature, 16h.

Step 1:3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (methylsulfanyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. The title compound was prepared by a procedure similar to that described for compound 1 using 3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid and 4-methyl-3- (methylthio) aniline. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.83(s,1H),8.63(s,1H),7.57(d,J＝2.0Hz,1H),7.40(dd,J＝8.1,2.0Hz,1H),7.34(dd,J＝89,5.0hz, 1H), 7.25 (dd, j=9.5, 3.0hz, 1H), 7.22-7.18 (m, 1H), 7.15 (td, j=8.5, 3.2hz, 1H), 2.46 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). LC-MS (method 1): m/z 451.9[ M+H ]]+,(ESI+),RT＝5.05。

Step 2:3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide prepared by a similar procedure to that described for compounds 104 and 105 using 3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (methylsulfanyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide with an excess of potassium hydrogen persulfate. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.19 (s, 1H), 8.65 (s, 1H), 8.34 (d, j=2.4 hz, 1H), 7.90 (dd, j=8.2, 2.4hz, 1H), 7.50 (d, j=8.4 hz, 1H), 7.34 (dd, j=9.0, 5.0hz, 1H), 7.25 (dd, j=9.4, 3.0hz, 1H), 7.15 (td, j=8.5, 3.1hz, 1H), 3.23 (s, 3H), 2.62 (s, 3H), 2.13 (s, 3H). LC-MS (method 1): m/z 451.9[ M+H ] ]+,(ESI+),RT＝5.05。

Compound 107:3- (4-fluoro-2-methoxyphenoxy) -N- (4-methyl-3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

3- (4-fluoro-2-methoxyphenoxy) -N- (4-methyl-3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide prepared by a similar procedure to that described for compound 1 using 3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid and 4-methyl-3- (methylthio) aniline and used in the next step. The title compound was prepared by a procedure similar to that described for compounds 104 and 105 using 3- (4-fluoro-2-methoxyphenoxy) -N- (4-methyl-3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.14 (s, 1H), 8.62 (s, 1H), 8.34 (d, j=2.3 hz, 1H), 7.91 (dd, j=8.3, 2.3hz, 1H), 7.50 (d, j=8.5 hz, 1H), 7.37 (dd, j=8.8, 5.8hz, 1H), 7.15 (dd, j=10.7, 2.9hz, 1H), 6.88 (td, j=8.5, 2.9hz, 1H), 3.73 (s, 3H), 3.23 (s, 3H), 2.62 (s, 3H). LC-MS (method 1): m/z 500.1[ M+H ]]+,(ESI+),RT＝4.33。

Compound 108:3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (methylsulfonyl) phenyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compounds 104 and 105 using 3- (2-ethoxy-4-fluorophenoxy) -6-methyl-N- (3- (methylthio) phenyl) pyridazine-4-carboxamide with excess potassium hydrogen persulfate. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.04 (s, 1H), 8.38 (t, j=1.7 hz, 1H), 7.95 (dt, j=7.7, 1.5hz, 1H), 7.88 (s, 1H), 7.71 (dt, j=7.8, 1.4hz, 1H), 7.68 (t, j=7.8 hz, 1H), 7.32 (dd, j=8.8, 5.9hz, 1H), 7.06 (dd, j=10.7, 2.9hz, 1H), 6.82 (td, j=8.5, 2.9hz, 1H), 3.97 (q, j=7.0 hz, 2H), 3.22 (s, 3H), 2.61 (s, 3H), 1.04 (t, j=7.0 hz, 3H). LC-MS (method 6): m/z 446.3[ M+H ]] ⁺ ,(ESI+),RT＝2.97。

Compound 109:3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (S-methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for step 3 of compound 93 using 3- (4-fluoro-2-methylphenoxy) -N- (4-methyl-3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.11 (s, 1H), 8.64 (s, 1H), 8.34 (d, j=2.3 hz, 1H), 7.89 (dd, j=8.2, 2.4hz, 1H), 7.43 (d, j=8.4 hz, 1H), 7.34 (dd, j=8.9, 5.0hz, 1H), 7.25 (dd, j=9.5, 2.9hz, 1H), 7.15 (td, j=8.5, 3.2hz, 1H), 4.29 (s, 1H), 3.08 (s, 3H), 2.66 (s, 3H), 2.13 (s, 3H). LC-MS (method 1): m/z:482.9[ M+H ] ]+,(ESI+),RT＝4.01。

Compounds 110 to 113 listed in table 24 were synthesized by a similar method as described for step 1 of compound 59 using the appropriate carboxylic acid and substituted aryl or heteroaryl aniline.

Table 24

Compounds 114 to 117 listed in table 25 were synthesized by a similar method as described for step 3 of compound 93 using the appropriate substituted compounds listed in table 24.

Table 25

Example 113

Compound 118:3- (2-chloro-5-fluorophenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: EDC, pyridine, room temperature, 16h.

A mixture of 3- (2-chloro-5-fluorophenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (0.100 g,0.316 mmol), 3-aminobenzene-1-sulfonamide (0.082 g,0.481 mmol) and EDC (0.0667 g,0.348 mmol) in pyridine (4 mL) was stirred at room temperature for 16h. The solvent was evaporated and the crude product was on SiO with a gradient of 0 to 100% EtOAc/hexanes ₂ Chromatography on this gave 3- (2-chloro-5-fluorophenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.086 g, 55.41%). ¹ H NMR(300MHz,DMSO-d ₆ ) δ11.18 (s, 1H), 8.76 (s, 1H), 8.30 (t, j=1.5 hz, 1H), 7.83 (dt, j=6.4, 2.4hz, 1H), 7.74 (dd, j=9.0, 5.7hz, 1H), 7.67-7.55 (m, 3H), 7.46 (s, 2H), 7.33 (ddd, j=9.0, 8.1,3.0hz, 1H). LC-MS (method 1): m/z 489.4[M-H] ⁺ 。

Compounds 119 to 129 listed in table 26 were synthesized by a similar method as described for compound 118 using the appropriate carboxylic acid and substituted aryl or heteroaryl aniline.

Table 26

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Example 114

Compound 130:3- (4-fluoro-2-hydroxyphenoxy) -N- (3- (methylsulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: trichloroborane (1.0M/DCM), tetrabutylammonium iodide, DCM, 0deg.C.

Trichloroborane (1.0M/DCM, 1.0mL,1.03 mmol), tetrabutylammonium iodide (42 mg,0.113 mmol) and 3- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (50 mg,0.103 mmol) were stirred in dry anhydrous DCM (0.515 mL) for 1h at 0 ℃ and cooled with an ice water bath. The reaction mixture was then concentrated under vacuum to obtain a crude residue. Purification by silica chromatography eluting with a gradient of EtOAc/heptane. The fractions with product were combined and concentrated. Chromatography on silica gel with 0% to 100% EtOAc/heptaneThe title compound (0.014 mg, 28%) was obtained as a white solid and was repurified by preparative LC. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.42 (bs, 1H), 10.42 (bs, 1H), 8.58 (s, 1H), 8.41-8.36 (m, 1H), 7.96 (dt, j=7.6, 1.7hz, 1H), 7.77-7.66 (m, 2H), 7.30 (dd, j=8.8, 6.0hz, 1H), 6.78-6.71 (m, 1H), 6.71-6.63 (m, 1H), 3.23 (s, 3H). (LC-MS (method 5)) m/z 472.0[ M+H ] ⁺ ,(ESI+),RT＝3.94。

Compound 131:3- (4-fluoro-2-hydroxyphenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound 3- (4-fluoro-2-hydroxyphenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.020g, 66%) as a white solid was prepared by a similar method described for compound 130 but from 3- (4-fluoro-2-methoxyphenoxy) -N- (3-sulfamoylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.15 (bs, 1H), 10.32 (bs, 1H), 8.59 (s, 1H), 8.31-8.28 (m, 1H), 7.84 (dt, j=6.6, 2.2hz, 1H), 7.64-7.57 (m, 2H), 7.43 (s, 2H), 7.30 (dd, j=8.8, 5.9hz, 1H), 6.77 (dd, j=10.2, 2.8hz, 1H), 6.74-6.65 (m, 1H). LC-MS (method 6): m/z:473.1[ M+H ]] ⁺ 。

Compound 132: n- (3-methanesulfonylphenyl) -3- [ 2-methyl-4- (1, 2-oxazol-4-yl) phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: KF. 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1, 2-oxazole, pd (dppf) Cl ₂ .DCM、DMF，60℃。

To 3- (4-bromo-2-methylphenoxy) -N- (3-methanesulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.050 g,0.094 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxanone at room temperatureTo a solution of pentaborane-2-yl) -1, 2-oxazole (0.022 g,0.113 mmol) in DMF (3 mL) was added KF (0.0164 g,0.283 mmol) to H ₂ O (0.200 mL). Deaeration by bubbling nitrogen for 10 minutes, add pd (dppf) Cl to the above mixture ₂ DCM (0.008 g,10 mol%) and the resulting mixture was heated at 60℃for 3h. At the end of this period, it was cooled to room temperature and water (5 mL) was added and extracted with EtOAc (2×20 mL). The combined organics were washed with water (20 mL) and 1M LiCl (20 mL). EtOAc layer over Na ₂ SO ₄ Dried, filtered, and the solvent evaporated under reduced pressure. SiO of the crude mixture in a gradient with 0 to 20% EtOAc/DCM ₂ Chromatographic analysis of the mixture to obtain N- (3-methanesulfonylphenyl) -3- [ 2-methyl-4- (1, 2-oxazol-4-yl) phenoxy]-6- (trifluoromethyl) pyridazine-4-carboxamide (0.021 g, 44%). ¹ H NMR(300MHz,DMSO-d ₆ ) δ11.29 (s, 1H), 9.48 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.38 (d, j=2.0 hz, 1H), 8.01-7.89 (m, 1H), 7.81-7.61 (m, 4H), 7.38 (d, j=8.4 hz, 1H), 3.25 (s, 3H), 2.18 (s, 3H). LC-MS (method 2): m/z 517.3[ M-H ]] ⁺ 。

Compound 133:3- [ 2-methyl-4- (1H-pyrazol-4-yl) phenoxy ] -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl ester, pd ₂ (dba) ₃ Xphos, 1, 4-dioxane, H ₂ O，40℃；b)LiOH、THF、H ₂ O, room temperature; c) (i) dmap.diea, 3- (methylsulfonyl) aniline, 50% propylphosphonic anhydride/EtOAc solution, DCM, rt; (ii) 4M HCl/dioxane, room temperature.

Step 1:3- [4- (1-tert-Butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester.

3- (4-bromo-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (100 mg,0.256 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-Pyrazole-1-carboxylic acid tert-butyl ester (75 mg,0.256 mmol), pd ₂ (dba) ₃ A suspension of (12 mg,0.0128 mmol) and Xphos (6.1 mg,0.0128 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen and stirred at 40℃for 18.5 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3X 20 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The compound was purified by column chromatography over silica using 0-100% etoac/heptane and rinsed with 0-60% meoh/DCM (on a Biotage Sfar 10g column, load compound onto silica dried using DCM) to give 3- [4- (1-tert-butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy as a pale yellow oil]-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (75.0%) (46 mg, 28%). ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 8.75 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.81 (d, j=1.6 hz, 1H), 7.69 (dd, j=8.3, 2.1hz, 1H), 7.27 (d, j=8.4 hz, 1H), 3.97 (s, 3H), 2.17 (s, 3H), 1.64-1.56 (m, 9H). LC-MS (method 3): m/z 379.2[ M+H ] ]+,(ESI+),RT＝1.03。

Step 2:3- [4- (1-tert-Butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester, lithium salt.

To a mixture of 3- [4- (1-tert-butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (75%, 46mg,0.0721 mmol) in THF (0.6 mL): water (0.1 mL) was added lithium hydroxide (4.5 mg,0.180 mmol) and the mixture was stirred at room temperature for 3h. The reaction was concentrated in vacuo to give 3- [4- (1-tert-butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy ] -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester, lithium salt (85.0%) (40 mg,0.0723mmol,100% yield) as a pale yellow solid. LC-MS (method 1): m/z 365.05[ m+h ] + (esi+), rt=0.97. This material was used in the next step without any further purification.

And 3, step 3. To 3- [4- (1-tert-butoxycarbonylpyrazol-4-yl) -2-methyl-phenoxy ] at room temperature]To a stirred solution of lithium 6- (trifluoromethyl) pyridazine-4-carboxylate (40 mg,0.0850 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.030 mL,0.170 mmol) and N, N-dimethylpyridine-4-amine (2.1 mg,0.0170 mmol) in DCM (0.6 mL) was added dropwise a 50% solution of propylphosphonic acid anhydride/EtOAc(50%, 0.061mL,0.102 mmol) and stirred for 10 minutes. 3- (methylsulfonyl) aniline (17 mg,0.102 mmol) was added in subsequent portions and stirred at room temperature for 1h. The reaction was treated with 50% propylphosphonic anhydride/EtOAc solution (50%, 0.061mL,0.102 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.030 mL,0.170 mmol) followed by DMF (0.1 mL) to promote dissolution. The reaction was stirred at room temperature for 16h. The reaction was treated again with a 50% solution of propylphosphonic anhydride/EtOAc (50%, 0.061ml,0.102 mmol) and stirred at room temperature for 2 hours. The reaction was again treated with N-ethyl-N-isopropyl-propan-2-amine (0.030 mL,0.170 mmol), N-dimethylpyridin-4-amine (2.1 mg,0.0170 mmol) and 50% propylphosphonic anhydride/EtOAc solution (50%, 0.061mL,0.102 mmol) and stirred at 45℃for 1h. The reaction was concentrated in vacuo and 4M HCl/dioxane (1.0 ml,4.00 mmol) was added and the reaction stirred at room temperature for 18h. The reaction mixture was poured into water (10 mL) and extracted with DCM (3×20 mL) and the combined organic phases were separated and concentrated in vacuo. The compound was purified by preparation 1, concentrated in vacuo and freeze-dried overnight to give the title compound 3- [ 2-methyl-4- (1H-pyrazol-4-yl) phenoxy as a white solid ]-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (6.0 mg, 14%). ¹ H NMR(400MHz,DMSO-d ₆ ) δ12.92 (s, 1H), 11.27 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.06 (s, 2H), 7.93 (d, j=7.7 hz, 1H), 7.69 (d, j=7.7 hz, 2H), 7.61 (d, j=1.7 hz, 1H), 7.53 (dd, j=8.3, 2.0hz, 1H), 7.25 (d, j=8.4 hz, 1H), 3.22 (s, 3H), 2.15 (s, 3H). LC-MS (method 6): m/z 518.3[ M+H ]] ⁺ ,(ESI+),RT＝2.94。

Compound 134:3- (4-fluoro-2-methyl-phenoxy) -N- ([ 1,2,4] triazolo [4,3-a ] pyridin-5-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Ammonium hydroxide (25%), 65 ℃; b) BrettPhos Pd G3, 5-bromo [1,2,4] triazolo [4,3-a ] pyridine, 1, 4-dioxane, cesium carbonate, 90 ℃.

Step 1.3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide

A suspension of 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (300 mg, 0.328 mmol) in ammonium hydroxide (25%, 1.9mL,45.4 mmol) was stirred at 65℃for 10min. The mixture was cooled to room temperature and the suspension was filtered and washed with water (5 ml×2) and dried under high vacuum at 40 ℃ for 2 hours to give the crude product. Purification using prep. method P3 gave the title compound (175 mg, 61%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ ) δ8.42 (s, 1H), 8.21 (d, j=5.3 hz, 2H), 7.31 (dd, j=8.9, 5.1hz, 1H), 7.25 (dd, j=9.4, 3.0hz, 1H), 7.15 (td, j=8.6, 3.1hz, 1H), 2.12 (s, 3H). LC-MS (method 6): m/z316.1[ M+H ]] ⁺ ,(ESI+),RT＝2.95。

Step 2.3- (4-fluoro-2-methyl-phenoxy) -N- ([ 1,2, 4)]Triazolo [4,3-a ]]Pyridin-5-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide: brettPhos Pd G3 (29 mg,0.0317 mmol), 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide (100 mg,0.317 mmol) and 5-bromo [1,2,4 ] at room temperature under nitrogen]Triazolo [4,3-a ]]A mixture of pyridine (94 mg,0.476 mmol) was dissolved in anhydrous 1, 4-dioxane (3 mL). The mixture was degassed with nitrogen for 5 min, then cesium carbonate (207 mg,0.634 mmol) was added in one portion. The reaction mixture was stirred at 90℃for 16h. The solvent was removed in vacuo and the crude residue was purified using preparative LC method P1 to give the title compound (95.0%) as a yellow solid (13 mg, 9.3%). ¹ H NMR(400MHz,DMSO-d ₆ ) δ11.66 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 7.72 (d, j=9.2 hz, 1H), 7.49 (dd, j=9.1, 7.3hz, 1H), 7.38 (s, 1H), 7.27 (dd, j=9.2, 2.8hz, 2H), 7.17 (td, j=8.5, 3.0hz, 1H), 2.16 (s, 3H). LC-MS (method 4): m/z 433.2[ M+H ]] ⁺ ,(ESI+),RT＝2.89。

Compound 135:3- (4-fluoro-2-methylphenoxy) -N- (tetrazolo [1,5-a ] pyridin-7-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

BrettPhos Pd G3 (29 mg, 0.03)17 mmol), (100 mg,0.317 mmol) and 7-bromotetrazolo [1,5-a ]]A mixture of pyridine (95 mg,0.476 mmol) was dissolved in anhydrous 1, 4-dioxane (3 mL). Cesium carbonate (207 mg,0.634 mmol) was then added in one portion and the suspension was degassed for 5min. The reaction mixture was stirred at 70℃for 2h. The mixture was filtered through a celite plug, washed with MeOH (5 mL) and the solvent was removed in vacuo. Purification by prep LC (method P1) gave the desired product (63 mg) with impurities. The material was then purified again using prep. method P3 to give the title compound (26 mg, 19%) as a pale yellow solid. ¹ H NMR(500MHz,DMSO-d ₆ ) δ11.67 (s, 1H), 9.30 (d, j=6.9 hz, 1H), 8.73 (s, 1H), 8.61-8.53 (m, 1H), 7.45 (dd, j=7.4, 2.1hz, 1H), 7.36 (dd, j=9.0, 5.0hz, 1H), 7.26 (dd, j=9.3, 2.9hz, 1H), 7.16 (td, j=8.5, 3.2hz, 1H), 2.14 (s, 3H). LCMS (method 5) m/z 434.1[ M+H ]]+,(ESI+),RT＝4.08。

Compound 136:3- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyrazine-2-carboxamide

Reagents and conditions: a) Titanium tetrachloride, tert-butyl nitrite, DCM,0 ℃; b) 3, 4-difluoro-2-methoxy-phenol, K ₂ CO ₃ Acetonitrile, 60 ℃; c) CuI, TBAI, methyl difluoro (fluorosulfonyl) acetate, DMF,70 ℃; d) LiOH, THF/H ₂ O, room temperature; e) HATU, DIEA, 3- (methylthio) aniline, DMF, room temperature; f) (NH) ₄ ) ₂ CO ₃ (diacetoxyiodo) benzene, meOH, room temperature

Step 1: 3-chloro-6-iodo-pyrazine-2-carboxylic acid methyl ester: to a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate (100 mg,0.358 mmol) in anhydrous DCM (1.5 mL) at 0deg.C was added titanium tetrachloride (38 uL,0.358 mmol) and the red solution was stirred for 5 min, then tert-butyl nitrite (90%, 95uL, 0.719 mmol) was added and the solution warmed to ambient temperature. After 30 minutes titanium tetrachloride (38 ul,0.358 mmol) was added and the mixture was stirred at ambient temperature for 1 hour, then analyzed by LCMS. Water (about 5 mL) was carefully added and the solution extracted with DCM (about 3X 5 mL). The organics were passed through a phase separator and the solvent removed in vacuo to give methyl 3-chloro-6-iodo-pyrazine-2-carboxylate (90.0%) as a pale yellow oil (103 mg,0.311mmol,87% yield). The material is used in crude form in a subsequent step.

Step 2:3- (3, 4-difluoro-2-methoxy-phenoxy) -6-iodo-pyrazine-2-carboxylic acid methyl ester: 3, 4-difluoro-2-methoxy-phenol (62 mg,0.387 mmol), 3-chloro-6-iodo-pyrazine-2-carboxylic acid methyl ester (110 mg,0.369 mmol) and K ₂ CO ₃ A mixture of (76 mg,0.553 mmol) in anhydrous acetonitrile (1.5 mL) was stirred overnight at 60 ℃. The reaction was filtered through a phase separator and washed with DCM (3X 10 mL), concentrated in vacuo and purified by FCC (10 g silica; 0-100% MTBE/heptane). The product fractions (trace of unimodal) were evaporated in vacuo to give 3- (3, 4-difluoro-2-methoxy-phenoxy) -6-iodo-pyrazine-2-carboxylic acid methyl ester (82.0%) as a colorless oil (55 mg,0.107mmol,29% yield).

¹ H NMR(400MHz,CD ₃ OD)δ8.53(s,1H),7.10-6.97(m,2H),4.00(s,3H),3.85-3.83(m,3H)m/z：423.0[M+H] ⁺ (esi+), rt=0.95 LCMS method 2.

Step 3:3- (3, 4-difluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyrazine-2-carboxylic acid methyl ester: to a mixture of methyl 3- (3, 4-difluoro-2-methoxy-phenoxy) -6-iodo-pyrazine-2-carboxylate (55 mg,0.130 mmol), copper iodide (37 mg,0.195 mmol) and ammonium N, N, N-tributylbutane-1-iodide (TBAI) (19 mg,0.0521 mmol) in anhydrous DMF (0.5 mL) was added methyl difluoro (fluorosulfonyl) acetate (0.083 mL,0.651 mmol) under N2. The reaction mixture was heated to 70 ℃ and stirred at this temperature for 3.5h. The reaction mixture was cooled to room temperature, filtered, poured into water and extracted with EtOAc (3 times). The combined organic phases were washed with brine (5 times), dried over MgSO4, filtered and concentrated in vacuo to give methyl 3- (3, 4-difluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyrazine-2-carboxylate (90.0%) as a dark brown oily solid (36 mg,0.0890mmol,68% yield). ¹ H NMR(500MHz,CD ₃ OD)δ8.59(s,1H),6.99-6.95(m,3H),3.94(s,3H),3.78-3.74(m,3H)。 ¹⁹ F NMR(471MHz,CD ₃ OD)δ-68.23,-140.04--141.07(m),-154.06--155.17(m)。

Step 4:3- (3, 4-difluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyrazine-2-carboxylic acid: to a mixture of methyl 3- (3, 4-difluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyrazine-2-carboxylate (39 mg,0.106 mmol) in THF (0.3 mL): water (0.1 mL) was added LiOH (21 mg,0.848 mmol) and the mixture stirred at room temperature for 38h. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (3×40 mL), passed through a phase separator and concentrated in vacuo. The product was used in the next step without any further purification.

Step 5:3- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyrazine-2-carboxamide: a mixture of 3- (3, 4-difluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyrazine-2-carboxylic acid (28 mg,0.0800 mmol), N-ethyl-N-isopropyl-propan-2-amine (DIEA) (0.028 mL,0.160 mmol), HATU (36 mg,0.0959 mmol) and 3- (methylthio) aniline (13 mg,0.0959 mmol) in DMF (0.1969 mL) was stirred at room temperature for 1h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were separated and concentrated in vacuo. The compound was purified by FCC using 0-100% etoac/heptane over silica (on a Biotage Sfar 10g column, using DCM to wet the supported compound) to give 3- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyrazine-2-carboxamide (55.0%) as a pale yellow solid (68 mg,0.0793mmol, 99%). m/z:472.1[ M+H ]] ⁺ (esi+), rt=1.07 LCMS method 2

Step 6:3- (3, 4-difluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]-6- (trifluoromethyl) pyrazine-2-carboxamide: to a suspension of 3- (3, 4-difluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyrazine-2-carboxamide (60%, 68mg,0.0866 mmol) in methanol (1 mL) was added (diacetoxyiodo) benzene (64 mg, 0.199mmol) and (NH ₄ ) ₂ CO ₃ (12 mg,0.130 mmol) and the reaction was stirred at room temperature for 4h. The reaction was concentrated in vacuo and purified using preparation 1. The eluate was evaporated in vacuo to give 3- (3, 4-difluoro-2-) -solid in the form of an off-white solidMethoxy-phenoxy) -N- [3- (methylsulfonyl) phenyl]-6- (trifluoromethyl) pyrazine-2-carboxamide (99.0%) (10 mg,0.0203mmol,23% yield). ¹ H NMR(400MHz,CD ₃ OD)δ8.75(s,1H),8.54(t,J＝1.9Hz,1H),8.09(dd,J＝8.1,1.2Hz,1H),7.89-7.82(m,1H),7.69(t,J＝8.0Hz,1H),7.18-7.05(m,2H),3.90(d,J＝1.7Hz,3H),3.20(s,3H)。m/z：501.3[M-H] ^- (ESI-), rt=3.07 LCMS method 4.

Example 115

Analysis of NaV1.8 Compound profiling-human NaV1.8 cell line-SyncroPatch 384PE

The compound was tested on HEK cells stably transfected with recombinant human nav1.8 using the syncopatch 384PE system (automated patch clamp device). Cells at 37℃C/5% CO ₂ The culture was performed in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS10% and inoculated in T175 flasks. Cells were cultured at 30 ℃ the day before recording sodium current. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium and placed in a syncopatch 384PE 6 ℃ pre-cooled cell hotel and shaken at 200 rpm. The intracellular solution (IC) contains the following in mM: 10, cscl;110, csf;20, EGTA;10, HEPES. The extracellular solution (EC) contained the following in mM: 140, naCl;4, KCl;5, glucose; 10, HEPES;2, caCl ₂ ；1，MgCl ₂ . The wash solution contained the following in mM: 40, nmdg;100, naCl;4, KCl;10, glucose; 10, HEPES;5, caCl ₂ ；1，MgCl ₂ 。

Compounds were tested in four replicates in 0.1% dmso and 0.03% pluronic acid. The compounds were diluted 1:3.33 in EC solution to generate a 10 point concentration response curve spanning a final concentration range of 10-0.0002 μm in the assay plate. Compounds with low nM potency can be retested using a lower concentration range (1 to 0.00002 μm). Each plate contained tetracaine and another tool compound as positive controls. Up to 7 compounds were tested on one plate. 150. Mu.M tetracaine and 0.1% DMSO were used as high and low controls, respectively.

According to the Nanion pairWhole cell patch clamp recordings were performed according to standard procedures of (2). The cells were held at a holding potential of-120 mV. A depolarization step of 10mV was applied for 30ms (P1 measurement), followed by a hyperpolarization step to-100 mV for 100ms. An inactivation step of 10 seconds was applied at-40 mV before stepping to-100 mV for 20ms, then stepping to 10mV for 30ms (P2 measurement), and then returning to-100 mV for 30ms. The scan interval was 15 seconds and the sampling rate was 10kHz. After establishment of the whole cell configuration in EC, two wash steps were performed with reference buffer to stabilize the baseline. The compound was then applied to each well by SynchroPatch and the current was recorded in EC for five minutes, followed by the application of tetracaine to obtain complete blocks at the end of the experiment. The efficacy of the compounds was evaluated for two readings (resting state block (P1 measurement) or inactive state block (P2 measurement)) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) control values.

Table 27 shows the potency of compounds against human NaV1.8, wherein "A" represents an IC50 of less than or equal to 200nM, "B" represents an IC50 of greater than 201nM to less than or equal to 500nM, "C" represents an IC50 of greater than 501nM to less than or equal to 1000nM, "D" represents an IC50 of greater than 1001nM to less than or equal to 5000nM, and "E" represents an IC50 of greater than 5001 nM.

Table 27

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D. Examples of the fourth group of Compounds

Example 116

The reaction was monitored by Thin Layer Chromatography (TLC) using 0.25mm silica gel 60F254 plates (ex EMD milleipore). Purification was performed with CombiFlash NextGen 300 automated flash chromatography system or purified using one of the preparative HPLC methods mentioned below.

Preparation method 1 (P1): early acid process

Preparation method 2 (P2): acid standard method

Preparation method 3 (P3): alkaline early stage method

Preparation method 4 (P4): alkaline standard method

LCMC was collected and analyzed using one of the following methods.

Method 1 (M1): acidic IPC method (METRR 1410-MS17, MS18, MS 19)

Method 2 (M2):

mass spectral data was collected using a Waters AcquityH-type ultra-high pressure liquid chromatograph connected to a Waters Acquity TQD mass spectrometer. Samples were separated and resolved using a Acquity UPLC BEH C column (2.1X50 mm). Compounds were eluted from the column using a 10min linear solvent gradient: 0-0.5min,5% B;0.5-6.5min,100% B,6.5-7.5min;100% B,7.5-8.1min;5% B,8.1-10min;5% B. The solvent flow rate was 0.45mL/min. Solvent a is water and solvent B is acetonitrile. Mass spectra were collected in either positive or negative ion mode with the following parameters: 2.5kV capillary voltage; 25V sampling cone voltage; source temperature of 140 ℃; desolvation temperature of 400 ℃;800L/hr of nitrogen desolvation.

Method 3 (M3): alkaline IPC method (MET-uPLC-AB-2005-MS 16, MSQ 5)

Method 4 (M4): acid final analysis method (METRR-uPLC-AB 101-MSQ1, MSQ2, MSQ 4)

Method 5 (M5): acid final analysis method (METRR 1416-MS18, MS 19)

Method 6 (M6): alkaline final analysis method (MET-uPLC-AB 105-MS16, MSQ 5)

SFC chiral resolution was performed using the following procedure: column: daicel CHIRALPAK IG,250mm×20mm I.D.,5 μm; mobile phase a: CO ₂ /MeOH[0.2％NH ₃ (7M MeOH solution)]=70/30; flow rate: 60g/min;214nm; temperature: 35 ℃.

Unless otherwise indicated, in Bruker ^TM 300MHz or 500MHz, 400MHz or 250MHz or in Bruker Avance III HD 500.500 MHz mass spectrometer, bruker Avance III HD 400.400 MHz massRecording on a spectrometer ¹ H Nuclear Magnetic Resonance (NMR) spectroscopy. Chemical shift δ is recited in parts per million (ppm) relative to TMS and is calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to represent multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet), dt (doublet of triplet), dq (doublet of quartet), hep (heptadoublet), m (multiplet), pent (quintet), td (doublet of doublet), qd (quartet of doublet), app (obvious) and br. (broad). The coupling constant J is given closest to 0.1 Hz.

Example 117

General synthetic scheme

Scheme A

Compounds of formula A-6 can be synthesized in a five-step linear synthesis starting from bischloroformate A-1 by using various substituted phenols in a base (e.g., K ₂ CO ₃ 、Cs ₂ CO ₃ Nucleophilic displacement of Cl adjacent to formate in the presence of NaH, KH or other organic base) to yield the a-2 intermediate. Form A-2 intermediate was further treated with HI (50%), HI (57%) or HI (40%) to give form A-3 intermediate. R is differently substituted ₃ The groups may be introduced by Pd-mediated or Cu-mediated coupling together with an intermediate of type A-3. Formic acid of the A-5 intermediate can be prepared by hydrolyzing an ester of the A-4 intermediate using a base (e.g., aqueous NaOH, KOH or LiOH). Alternatively, the A-5 type intermediate may be prepared by using 1 to 6N aqueous HCl Processing the intermediate of form A-4. The carboxylic acid (A-5) can be activated to acid chloride and is reacted with R ₂ NH ₂ Coupling or carboxylic acid (A-5) can use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to give A-6.

Scheme B

Alternatively, compounds of formula A-6 may be prepared using various substituted phenols in a base (e.g., K ₂ CO ₃ 、Cs ₂ CO ₃ NaH, KH or other organic base) by nucleophilic displacement of Cl of the B-1 intermediate, to give the B-2 intermediate. Formic acid of the B-3 intermediate can be prepared by hydrolyzing esters of the B-2 intermediate using a base (e.g., aqueous NaOH, KOH or LiOH). Alternatively, the B-3 form intermediate may be prepared by treating the B-2 form intermediate with 1 to 6N aqueous HCl. The carboxylic acid (B-3) can be activated to acid chloride and is reacted with R ₂ NH ₂ Coupling or carboxylic acid (B-3) can use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to give A-6.

Scheme C

Alternatively, the A-6 type compound may also be prepared by: activating carboxylic acid (C-1) to acid chloride and reacting with R ₂ NH ₂ Coupling or carboxylic acid (C-1) can use standard amide coupling agents (not limited to HATU, TBTU, EDC or T ₃ P) in an organic solvent and a base (e.g., DIEA, et) ₃ N, DMAP or pyridine) with R ₂ NH ₂ Coupling to obtain C-2. The A-6 type compound can be prepared by using an organic solvent in the presence of a base (e.g., naH, K ₂ CO ₃ 、Cs ₂ CO ₃ DIEA or Et ₃ N) treatment of the C-2 intermediates with various phenols.

Example 118

Specific synthesis:

Reagents and conditions: a) 4-fluoro-2-methoxy-phenol, K ₂ CO ₃ 、CH ₃ CN,60 ℃ for 7 hours; b) HI (55%), 40℃for 24h; c) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, TBAI, cuI, DMF,90 ℃ for 2h; d) LiOH, THF, H ₂ O, room temperature, 24h.

A mixture of 4-fluoro-2-methyl-phenol (3.01 g,23.8 mmol), methyl 3, 6-dichloropyridazine-4-carboxylate (4.70 g,22.7 mmol) and potassium carbonate (4.71 g,34.1 mmol) in acetonitrile (47 mL) was stirred at 80℃for 3h.

The reaction was cooled to room temperature, filtered and washed with MeCN (20 mL). The filtrate was concentrated in vacuo to give a crude residue. Purification by silica gel chromatography eluting with a gradient of 0% to 15% etoac/heptane afforded the title compound methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (95.0%) as a pale yellow oil (4.10 g, 58%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.26(s,1H),7.29-7.20(m,2H),7.16-7.06(m,1H),3.94(s,3H),2.11(s,3H)。LC-MS：m/z：297/299[M+H] ⁺ 。

Step 2:3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester.

A mixture of 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid methyl ester (95%, 4.10g,13.1 mmol) in 55% aqueous hydrogen iodide (50 mL, 0.197mol) was stirred at 40℃for 3h. The mixture was left to stand overnight at room temperature. The reaction mixture was filtered. The filter cake was washed with water. The solid was redissolved in 55% aqueous hydrogen iodide (50 mL, 0.197mol) andstirred at 40℃for 24h. The mixture was cooled to room temperature and filtered, the solid was washed with water and dried overnight in a high vacuum oven at 40 ℃ to give 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester (79.0%) as a yellow solid (2.70 g, 42%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.37(s,1H),7.26-7.17(m,2H),7.15-7.05(m,1H),3.91(s,3H),2.09(s,3H)。MS:m/z：388.9[M+H] ⁺ 。

Step 3:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 3- (4-fluoro-2-methyl-phenoxy) -6-iodo-pyridazine-4-carboxylate (80%, 2.70g,5.57 mmol), cuI (1.6 g,8.35 mmol), tetrabutylammonium iodide (0.284 g,2.23 mmol) in DMF (10 mL) (degassed with nitrogen for 5 min) was added difluoro (fluorosulfonyl) acetate (5.34 g,27.8 mmol) and stirred at 90 ℃ for 2h. The reaction was cooled to room temperature, filtered and washed with EtOAc (2×10 mL). The filtrate was washed with brine (50 mL) and over MgSO ₄ Drying, filtration and concentration under reduced pressure gave a crude residue. Purification by silica chromatography eluting with a gradient of 0 to 50% etoac/heptane afforded the title compound methyl 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (99.0%) as a pale yellow solid (0.770 mg, 41%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.54(s,1H),7.32-7.20(m,2H),7.14(td,J＝8.5,3.2Hz,1H),3.97(s,3H),2.13(s,3H)。MS:m/z：316.95[M+H]++ (ESI+). Unreacted starting material, methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (220 mg, 13%) was recovered as a pale yellow oil.

Step 4:3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid.

To a mixture of methyl 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylate (99%, 770mg,2.31 mmol) in THF (7.92 mL): water (1.98 mL) was added lithium hydroxide (288 mg,11.5 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solid was filtered, washed with water (2X 10 mL), dissolved in EtOAc (20 mL) and taken up in Na ₂ SO ₄ Dried and concentrated under reduced pressure to give the title compound as an off-white solidThe product 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (99.0%) (640 mg, 87%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.49(s,1H),7.31-7.22(m,2H),7.18-7.09(m,1H),2.12(s,3H)。LC-MS：m/z 316.95[M+H] ⁺ (esi+), rt=1.06 method METCR1410 is typically 2min.

Intermediate 2:3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid

Reagents and conditions: a) 4-fluoro-2-methoxy-phenol, K ₂ CO ₃ 、CH ₃ CN，60℃，7h；b)SOCl ₂ MeOH, 50 ℃; c) HI (55%), 40℃for 24h; d) Methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate, TBAI, cuI, DMF,90 ℃ for 2h; e) LiOH, THF, H ₂ O, room temperature, 24h.

Step 1: 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylic acid.

To a solution of 4-fluoro-2-methoxyphenol (1.2 mL,10.4 mmol) in DMF (20.7 mL) was added sodium hydride (60%) (0.622 g,15.5 mmol) under nitrogen and the solution was stirred at room temperature for 30min. 3, 6-dichloropyridazine-4-carboxylic acid (1.00 g,5.18 mmol) was added to the resulting mixture and stirring was continued at room temperature for 66 hours. At the end of this period, water (200 mL) was added and the pH was adjusted to 1 with HCl (6N). The mixture was extracted with EtOAc (4X 40 mL). The combined extracts were purified by Na ₂ SO ₄ Dried, filtered and concentrated. The crude mixture was purified by column chromatography over SiO with a gradient of 0-80% EtOAc/heptane ₂ Purification was performed to give the title compound 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylic acid (1.211 g, 74%) as a pale red solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ8.32(s,1H),7.27(dd,J＝8.8,5.8Hz,1H),7.12(dd,J＝10.7,2.9Hz,1H),6.84(td,J＝8.5,2.9Hz,1H),3.71(s,3H)。LC-MS：m/z 299.0/301.0[M+H] ⁺ ,(ESI+)。

Step 2: 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylic acid methyl ester.

6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylic acid (500 mg,1.77 mmol) was dissolved in DCM (12.2 mL), thionyl chloride (5.1 mL,70.8 mmol) was added in one portion at room temperature and the resulting mixture was stirred at 50℃for 8h. Additional thionyl chloride (2.5 mL,35 mmol) was added and the reaction stirred at 50deg.C for an additional 1 hour. The mixture was cooled to 0 ℃ and anhydrous methanol (5.48 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30min. The reaction mixture was diluted with water (20 mL) followed by saturated Na ₂ CO ₃ Aqueous solution (20 mL) was diluted, and the layers were separated and the organic layer was dried (MgSO ₄ ) Filtered and concentrated in vacuo. The crude residue was purified by silica chromatography eluting with a gradient of EtOAc/heptane to give methyl 6-chloro-3- (4-fluoro-2-methyl-phenoxy) pyridazine-4-carboxylate (335 mg, 64%) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.25(s,1H),7.25-7.18(m,2H),7.10(td,J＝8.6,3.1Hz,1H),3.92(s,3H),2.09(s,3H)。LC-MS：m/z 297.3[M+H] ⁺ (esi+), rt= 1.21METCR1410 is typically 2min.

Step 3:3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester.

A mixture of methyl 6-chloro-3- (4-fluoro-2-methoxy-phenoxy) pyridazine-4-carboxylate (8.10 g,23.3 mmol) in 55% aqueous hydrogen iodide (18 mL,0.350 mol) was stirred at 40℃for 24h. The mixture was cooled to room temperature and filtered. The solid was washed with water and dried overnight in a high vacuum oven at 40 ℃ to give the title compound 3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylic acid methyl ester (12.58 g, 88%) as an orange solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.35(s,1H),7.25(m,1H),7.13-7.09(m,1H),6.84-6.79(m,1H),3.90(s,3H),3.70(s,3H)。LC-MS：m/z：404.9[M+H]+, (esi+), rt=1.19, meta 1410 typically 2min.

Step 4:3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester: to a mixture of methyl 3- (4-fluoro-2-methoxy-phenoxy) -6-iodo-pyridazine-4-carboxylate (13.34 g,21.8 mmol), copper iodide (6.26 g,32.7 mmol), tetrabutylammonium iodide (3.23 g,8.71 mmol) in DMF (72 mL) (degassed with nitrogen for 5 min) was added methyl difluoro (fluorosulfonyl) acetate(20.92 g,0.109 mol) and stirred at 90℃for 2h. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (4X 100 mL). The combined organic layers were washed with (50 mL) and brine (50 mL) water over Na ₂ SO ₄ Drying, filtration, and evaporation of the solvent under reduced pressure gave a crude residue. Purification by silica chromatography eluting with a gradient of 0 to 50% etoac/heptane afforded the title compound (95.0%) as a pale orange solid (2.85 g, 36%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.53(s,1H),7.32(dd,J＝8.8,5.8Hz,1H),7.16(dd,J＝10.7,2.9Hz,1H),6.87(td,J＝8.5,2.9Hz,1H),3.96(s,3H),3.72(s,3H)。LC-MS：m/z 347.3[M+H] ⁺ (esi+), rt=3.57 MET-uPLC-AB-105 (7 min, high pH).

Step 5:3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid.

To 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester (2.85 g,7.82 mmol) in THF: H ₂ To a mixture in O (4:1; v/v) (40 mL) was added lithium hydroxide (0.98 g,39.1 mmol) and the mixture was stirred at room temperature for 24h. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The product was extracted with EtOAc (3X 60 mL) and dried (MgSO ₄ ) Filtration and evaporation of the solvent under reduced pressure gave the title compound 3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (90.0%) as an orange solid (2.35 g, 82%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.11(s,1H),7.24(dd,J＝8.8,5.9Hz,1H),7.12(dd,J＝10.7,2.8Hz,1H),6.84(dt,J＝8.5,4.2Hz,1H),3.71(s,4H)。LC-MS：m/z 332.95[M+H] ⁺ (esi+), rt=1.03 method XX METCR1410 is typically 2min.

Example 119

Compound 1: (R) -3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) piperidine-1-carboxylic acid tert-butyl ester

Reagents and conditions: (3R) -3-aminopiperidine-1-carboxylic acid tert-butyl ester, HATU, DIEA, DCM, room temperature, 2h.

A mixture of N-ethyl-N-isopropyl-propan-2-amine (0.12 mL,0.696 mmol), 3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (100 mg,0.316 mmol) and tert-butyl (3R) -3-aminopiperidine-1-carboxylate (76 mg,0.379 mmol) was dissolved in DCM (5 mL) under nitrogen at room temperature. N- [ (dimethylamino) (3H- [1,2, 3) was added in one portion]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]N-methyl ammonium hexafluorophosphate (144 mg,0.379 mmol). The reaction mixture was stirred at room temperature for 2h. The solvent was reduced to 2mL in vacuo. Purification by silica gel chromatography eluting with a gradient of 0% to 100% etoac/heptane afforded (3R) -3- [ [3- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridazine-4-carbonyl ] as an off-white solid ]Amino group]Tert-butyl piperidine-1-carboxylate (95.0%) (140 mg,0.267mmol,84% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.76(d,J＝7.5Hz,1H),8.37(s,1H),7.30(dd,J＝9.0,5.0Hz,1H),7.25(dd,J＝9.3,3.1Hz,1H),7.15(dt,J＝8.5,4.3Hz,1H),3.89-3.77(m,2H),3.60-3.51(m,1H),3.09-2.92(m,2H),2.12(s,3H),1.93-1.84(m,1H),1.73-1.65(m,1H),1.59-1.30(m,11H)。LC-MS：m/z 496.95[M-H] ⁺ (ESI-), rt= 1.36METCR1410 is typically 2min.

Compound 2: (R) -3- (4-fluoro-2-methylphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) 2, 2-trifluoroacetic acid, DCM, room temperature, 3h.

Tert-butyl (R) -3- (3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide) piperidine-1-carboxylate (0.130 g,0.248 mmol) and 2, 2-trifluoroacetic acid (0.37 mL,4.96 mmol) were stirred under nitrogen at room temperature in DCM (3.92 mL). The reaction mixture was stirred at room temperature for 3h. The solvent was removed in vacuo and the residue was dissolved in DCM (10 mL) with saturated NaHCO ₃ (10 mL) and brine (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title as an off-white solidThe compound (R) -3- (4-fluoro-2-methylphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.075 g, 72%). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.67(d,J＝7.9Hz,1H),8.41(s,1H),7.31(dd,J＝8.9,5.0Hz,1H),7.25(dd,J＝9.3,3.1Hz,1H),7.14(td,J＝8.5,3.1Hz,1H),3.89-3.79(m,1H),2.96(dd,J＝11.8,3.4Hz,1H),2.71(dt,J＝12.1,4.3Hz,1H),2.48-2.42(m,2H),2.31-2.18(m,1H),2.13(s,3H),1.89-1.79(m,1H),1.67-1.56(m,1H),1.52-1.34(m,2H)。LC-MS：m/z 399.0[M+H]+, (esi+), rt=2.95 MET-uPLC-AB-101 (7 min, low pH).

Compound 3: (R) -3- (4-fluoro-2-methylphenoxy) -N- (1- (methylsulfonyl) piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: meSO ₂ Cl、DMAP、Et ₃ N, DCM, room temperature.

A mixture of triethylamine (0.015 mL,0.107 mmol), (R) -3- (4-fluoro-2-methylphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.030 g,0.0715 mmol) and methanesulfonyl chloride (0.0083 mL,0.107 mmol) was dissolved in DCM (2 mL) under nitrogen at room temperature. N, N-lutidine-4-amine (8.7 mg,0.0715 mmol) was added to the above mixture and stirred continuously at room temperature for 1h. The solvent was removed in vacuo. Purification by preparative LC gave the title compound (R) -3- (4-fluoro-2-methylphenoxy) -N- (1- (methylsulfonyl) piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.019 g, 57%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.87(d,J＝7.7Hz,1H),8.41(s,1H),7.30(dd,J＝8.9,5.1Hz,1H),7.24(dd,J＝9.4,3.0Hz,1H),7.14(td,J＝8.6,3.1Hz,1H),4.09-3.96(m,1H),3.56(dd,J＝11.4,3.7Hz,1H),3.32-3.22(m,1H),2.97-2.89(m,1H),2.87(s,3H),2.82(dd,J＝11.4,8.3Hz,1H),2.12(s,3H),1.90-1.78(m,2H),1.66-1.46(m,2H)。LC-MS：m/z 477.0[M+H]+, (esi+), rt=4.1 MET-uPLC-AB-101 (7 min, low pH). Early elution method-column: sunfire TM preparation type C18 10um OBDTM, 30X 100mm; mobile phase: 5-95% acetonitrile (0.1% formic acid)/water (0).1% formic acid) for 14 minutes; flow rate: 40mL/min; UV:215 and 254 nm)

Compound 4: (R) -N- (1-acetylpiperidin-3-yl) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) Ac (Ac) ₂ O、Et ₃ N, DCM, DMAP, room temperature.

A mixture of acetic anhydride (0.0099 mL,0.107 mmol), (R) -3- (4-fluoro-2-methylphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.030 g,0.0715 mmol) and triethylamine (0.015 mL,0.107 mmol) was dissolved in DCM (2 mL) under nitrogen at room temperature and DMAP (0.0087 g, 7.15. Mu. Mol) was added. The reaction mixture was stirred at room temperature for 1h. The solvent was removed in vacuo. Purification by preparative LC method a gave the title compound (R) -N- (1-acetylpiperidin-3-yl) -3- (4-fluoro-2-methylphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide (0.015 g, 49%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.52(bs,1H),8.30(s,1H),7.28(dd,J＝8.9,5.0Hz,1H),7.20(dd,J＝9.4,3.1Hz,1H),7.10(td,J＝8.5,3.1Hz,1H),4.04-3.74(m,2H),3.59-3.49(m,1H),3.40-3.19(m,2H),2.15(s,3H),2.02-1.91(m,4H),1.78-1.61(m,2H),1.59-1.44(m,1H)。LC-MS：m/z 441.0[M+H]+, (esi+), rt=3.94 MET-uPLC-AB-101 (7 min, low pH).

Compound 5: (S) -3- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) piperidine-1-carboxylic acid tert-butyl ester

Reagents and conditions: (3S) -3-aminopiperidine-1-carboxylic acid tert-butyl ester, DIEA, DCM, room temperature.

3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (140 mg, 0.426 mmol) tert-butyl (3S) -3-aminopiperidine-1-carboxylate [. Sup.101mg,0.506 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.16 mL,0.927 mmol) were dissolved in DCM (2.1071 mL). N- [ (dimethylamino) (3H- [1,2, 3) was added in one portion]Triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]N-methyl ammonium hexafluorophosphate (192 mg,0.506 mmol). The reaction mixture was stirred at room temperature for 2h. IPC1 LCMS showed formation of the desired product. The reaction mixture was purified directly by silica chromatography (Sfar Duo 10 g) eluting with a gradient of 0 to 50% etoac/heptane to give (3S) -3- [ [3- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridazine-4-carbonyl as a colorless oil]Amino group]Piperidine-1-carboxylic acid tert-butyl ester (95.0%) (182 mg, 80%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(d,J＝7.6Hz,1H),8.34(s,1H),7.34(dd,J＝8.8,5.9Hz,1H),7.16(dd,J＝10.7,2.9Hz,1H),6.88(td,J＝8.5,2.9Hz,1H),3.90-3.76(m,2H),3.73(s,3H),3.58-3.51(m,1H),3.09-2.96(m,2H),1.97-1.84(m,1H),1.77-1.65(m,1H),1.61-1.41(m,2H),1.37(s,9H)。m/z513.6[M+H]+, (esi+), rt=4.06 MET-uPLC-AB-105 (7 min, high pH).

Compound 6: (S) -3- (4-fluoro-2-methoxyphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

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The title compound was prepared by a procedure similar to that described for compound 2 using (S) -3- (3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamido) piperidine-1-carboxylic acid tert-butyl ester. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(d,J＝7.8Hz,1H),8.37(s,1H),7.35(dd,J＝8.8,5.9Hz,1H),7.15(dd,J＝10.7,2.9Hz,1H),6.88(td,J＝8.5,2.9Hz,1H),3.96-3.76(m,2H),3.73(s,3H),2.99(m,2H),2.75(m,1H),2.46(m,1H),1.84(m,1H),1.63(s,1H),1.56-1.33(m,2H)。m/z 415.3[M+H]+, (esi+), rt=3.09 MET-uPLC-AB-105 (7 min, high pH).

Compound 7: (S) -3- (4-fluoro-2-methoxyphenoxy) -N- (1- (methylsulfonyl) piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide

Reagents and conditions: a) MeSO ₂ Cl, DMAP, DCM, room temperature, 1h.

The title compound was prepared by a procedure similar to that described for compound 3 using (S) -3- (4-fluoro-2-methoxyphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide and methanesulfonyl chloride. ¹ H NMR(500MHz,DMSO-d ₆ )δ8.83(d,J＝7.7Hz,1H),8.38(s,1H),7.34(dd,J＝8.8,5.8Hz,1H),7.15(dd,J＝10.7,2.9Hz,1H),6.87(td,J＝8.5,2.9Hz,1H),4.00(m,1H),3.72(s,3H),3.57(dd,J＝11.2,3.9Hz,2H),2.94-2.88(m,1H),2.87(s,3H),2.80(dd,J＝11.3,8.4Hz,1H),1.91-1.76(m,2H),1.65-1.45(m,2H)。m/z 492.9[M+H]+,(ESI+),RT＝4.06METCR1416 Hi res 7min。

Compound 8: (S) -N- (1-acetylpiperidin-3-yl) -3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxamide

The title compound was prepared by a procedure similar to that described for compound 4 using (S) -3- (4-fluoro-2-methoxyphenoxy) -N- (piperidin-3-yl) -6- (trifluoromethyl) pyridazine-4-carboxamide and acetic anhydride. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.45(s,1H),8.28(s,1H),7.33(dd,J＝8.8,5.8Hz,1H),7.10(dd,J＝10.6,2.9Hz,1H),6.86(td,J＝8.5,2.9Hz,1H),4.03-3.85(m,2H),3.74(s,3H),3.60-3.45(m,1H),3.25(d,J＝34.9Hz,2H),1.97(s,3H),1.95-1.87(m,1H),1.68(dd,J＝11.5,7.7Hz,2H),1.51(s,1H)。m/z 457.0[M+H]+,(ESI+),RT＝3.85METCR1416 Hi res 7min。

The compounds listed in table 28 were prepared by a similar procedure as described for compound 1 using the appropriate starting materials.

Table 28

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Example 120

Analysis of NaV1.8 Compound profiling-human NaV1.8 cell line-SyncroPatch 384PE

According to the Nanion pairWhole cell patch clamp recordings were performed according to standard procedures of (2). The cells were held at a holding potential of-120 mV. A depolarization step of 10mV was applied for 30ms (P1 measurement), followed by a hyperpolarization step to-100 mV for 100ms. An inactivation step of 10 seconds was applied at-40 mV before stepping to-100 mV for 20ms, then stepping to 10mV for 30ms (P2 measurement), and then returning to-100 mV for 30ms. The scan interval was 15 seconds and the sampling rate was 10kHz. After establishment of the whole cell configuration in EC, two wash steps were performed with reference buffer to stabilize the baseline. The compound was then applied to each well by SynchroPatch and the current was recorded in EC for five minutes, followed by the application of tetracaine to obtain complete blocks at the end of the experiment. The efficacy of the compounds was evaluated for two readings (resting state block (P1 measurement) or inactive state block (P2 measurement)) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) control values. Table 28 shows the potency of the compounds relative to nav 1.8.

Table 29 shows the potency of compounds against human NaV1.8, wherein "A" represents an IC50 of less than or equal to 200nM, "B" represents an IC50 of greater than 201nM to less than or equal to 500nM, "C" represents an IC50 of greater than 501nM to less than or equal to 1000nM, "D" represents an IC50 of greater than 1001nM to less than or equal to 5000nM, and "E" represents an IC50 of greater than 5001 nM.

Table 29

Compounds of formula (I)	P1 IC50	P2 IC50
			1	E	E
3	E	E
			4	E	E
5	E	E
			6	E	E
7	E	E
			8	E	E
9	E	E
			10	E	E
11	E	E
			12	E	E

E. Examples of the fifth group of Compounds

Example 121

Synthesis procedure

Exemplary compounds are prepared via several general synthetic routes set forth in the examples below. Any of the disclosed compounds of the present invention may be prepared according to one or more of these synthetic pathways or specific examples or via modifications thereof that may be obtained by one of ordinary skill in the art.

Method A

Step 1: 4-bromo-6- (trifluoromethyl) pyridazin-3 (2H) -one

6- (trifluoromethyl) pyridazin-3 (2H) -one (9.00 g,54.8mmol,1.00 eq), 4 angstrom molecular sieve (18.0 g) and dibromohydantoin (20.3 g,71.3mmol,1.30 eq) were added to acetic acid (37.0 mL) and acetonitrile (863 mL) and the mixture was stirred at 60℃for 48H. The reaction mixture was diluted with water (1.00L) and extracted with ethyl acetate (500 mL. Times.3). The combined organic layers were washed with brine (1.50L), and dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=50/1 to 15/1) to give the desired product as a yellow solid (7.00 g,28.8mmol,52.5% yield).

¹ H NMR:400MHz CDCl ₃ δ-12.22(s,1H),7.86(s,3H)。

MS,ES ⁺ m/z 243(M+H) ⁺

Step 2: 3-oxo-6- (trifluoromethyl) -2, 3-dihydropyridazine-4-carboxylic acid methyl ester

To 4-bromo-6- (trifluoromethyl) pyridazin-3 (2H) -one (5.00 g,20.5mmol,1.00 eq.) in methanol (10)0 mL) was added Xantphos (500 mg, 864. Mu. Mol,0.042 eq.) Pd (OAc) ₂ (115 mg,514umol,0.0250 eq) and triethylamine (4.16 g,41.1mmol,5.73mL,2.00 eq) were placed in an autoclave and the mixture was stirred at 80℃under CO (50 psi) for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=30/1 to 0/1) to give the desired compound (2.50 g,11.2mmol,54.7% yield) as a yellow solid.

¹ H NMR:400MHz CDCl ₃ δ12.54(s,1H),8.11(s,1H),3.99(s,3H)。

MS,ES ⁺ m/z 223(M+H) ⁺

Step 3: 3-chloro-6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester

To a solution of 3-oxo-6- (trifluoromethyl) -2, 3-dihydropyridazine-4-carboxylic acid methyl ester (1.50 g,6.75mmol,1.00 eq.) in 1, 4-dioxane (15.0 mL) was added phosphorus oxychloride (10.3 g,67.5mmol,6.28mL,10.0 eq.) at 0deg.C and the mixture was stirred at 100deg.C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ Petroleum ether/ethyl acetate=50/1 to 8/1) to give the desired product (1.00 g,4.16mmol,61.6% yield) as a yellow oil.

¹ H NMR:400MHz CDCl ₃ δ-8.17(s,1H),4.06(s,3H)。

MS,ES ⁺ m/z 241(M+H) ⁺

Step 4:3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid methyl ester

To a solution of methyl 3-chloro-6- (trifluoromethyl) pyridazine-4-carboxylate (500 mg,2.1 mmol) in acetonitrile (10 mL) was added 4-fluoro-2-methoxy-phenol (325 mg,2.3mmol,1.1 eq.) and cesium carbonate (680 mg,2.1mmol,1.0 eq.). The resulting mixture was heated to 50 ℃ for 2 hours. After cooling to room temperature, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product. Was used without further purification, and quantitative yields were assumed.

MS,ES ⁺ m/z 347(M+H) ⁺

Step 5:3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid

The crude product of step 4 (719 mg,2.1 mmol) was dissolved in methanol (15 mL) and water (5 mL) and excess sodium hydroxide solid was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water (75 mL) and the pH was adjusted to about 2 by careful addition of 6N hydrochloric acid, allowing a precipitate to form. Collected by filtration, washed with water and dried under reduced pressure to give the desired product (350 mg,1.1mmol,51% yield) as a white solid.

MS,ES ⁺ m/z 333(M+H) ⁺

Step 6:3- (4-fluoro-2-methoxyphenoxy) -N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

3- (4-fluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-4-carboxylic acid (350 mg,1.1 mmol) was dissolved in dichloromethane (5 mL). Oxalyl chloride (0.1 mL,1.2 mmol) and N, N-dimethylformamide (1 drop) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath, and 3-methylthioaniline (161 mg,1.2 mmol) and N, N-diisopropylethylamine (272 mg,2.1 mmol) were added dropwise as a solution in dichloromethane (5 mL). The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO ₂ Dichloromethane/methanol, 0-5%) to give the desired product as a solid (355 mg,0.8mmol,74% yield).

MS,ES ⁺ m/z 454(M+H) ⁺

Step 7:3- (4-fluoro-2-methoxyphenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide

To 3- (4-fluoro-2-methoxyphenoxy) -N- (3- (methylthio) phenyl) -6- (trifluoromethyl) pyridazine-4-carboxamide (355 mg,0.8 mmol) in methanolTo a solution of (10 mL) was added ammonium carbonate (113 mg,1.2mmol,1.5 eq.) and iodobenzene diacetate (580 mg,1.8mmol,2.3 eq.). The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO ₂ Dichloromethane/methanol, 0-12%) to give the desired product as a solid (189 mg,0.4mmol,50% yield).

¹ H NMR(400MHz,DMSO-d6)d ppm 3.07(d,J＝0.76Hz,3H)3.74(s,3H)4.29(s,1H)6.83-6.94(m,1H)7.17(dd,J＝10.74,2.91Hz,1H)7.39(dd,J＝8.84,5.81Hz,1H)7.65(t,J＝7.96Hz,1H)7.69-7.77(m,1H)7.93(ddd,J＝8.02,2.08,1.01Hz,1H)8.36(t,J＝1.89Hz,1H)8.65(s,1H)11.21(s,1H)。

MS,ES ⁺ m/z 485(M+H) ⁺

Method B

Step 1: 6-chloro-3- (4- (trifluoromethoxy) phenoxy) pyridazine-4-carboxylic acid methyl ester

To a solution of methyl 3, 6-dichloropyridazine-4-carboxylate (1.5 g,7.2 mmol) in acetonitrile (15 mL) was added 4- (trifluoromethoxy) phenol (1.4 g,8.0 mmol) and cesium carbonate (2.4 g,7.2 mmol). The resulting mixture was stirred at 40℃for 1 hour, followed by dilution with water (100 mL). The mixture was extracted with ethyl acetate (25 ml×3), and the combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (SiO ₂ Heptane/ethyl acetate, gradient 0-50%) to give the desired product as an oil (1.2 g,3.4mmol,47% yield) which solidifies on standing.

MS,ES ⁺ m/z 349(M+H) ⁺

Step 2: 6-chloro-3- (4- (trifluoromethoxy) phenoxy) pyridazine-4-carboxylic acid

To a solution of methyl 6-chloro-3- (4- (trifluoromethoxy) phenoxy) pyridazine-4-carboxylate (1.2 g,3.4 mmol) in methanol (15 mL) was added water (5 mL) and excess sodium hydroxide solid. The resulting mixture was stirred at room temperature for 1.5 hours, then diluted with water (75 mL). The pH was adjusted to about 1 by careful addition of 6N hydrochloric acid so that a precipitate formed. The precipitate was collected by filtration, washed with water and sucked dry to give the desired product as a colourless solid (365 mg,1.1mmol,32% yield).

MS,ES ⁺ m/z 335(M+H) ⁺

Step 3: 6-chloro-N- (3- (methylsulfonyl) phenyl) -3- (4- (trifluoromethoxy) phenoxy) pyridazine-4-carboxamide

6-chloro-3- (4- (trifluoromethoxy) phenoxy) pyridazine-4-carboxylic acid (365 mg,1.1 mmol) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.14 mL,1.6 mmol) was added followed by a single drop of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 1 hour, and then cooled in an ice bath. 3- (methylsulfonyl) aniline (225 mg,1.3 mmol) and triethylamine (0.15 mL,1.1 mmol) were added dropwise as a solution in dichloromethane (5 mL) and the mixture was warmed to room temperature. Volatiles were removed under reduced pressure and the resulting residue was purified by preparative RP-HPLC (water/acetonitrile, 5-95% gradient) to give the desired product (239 mg,0.49mmol,45% yield) as a colorless solid.

¹ H NMR(400MHz,DMSO-d ₆ ):d ppm 3.24(s,3H)7.41-7.55(m,4H)7.65-7.78(m,2H)7.94(dt,J＝7.83,1.64Hz,1H)8.31-8.39(m,2H)11.24(s,1H)

MS,ES ⁺ m/z 488(M+H) ⁺

The following compounds of formula (I-IV) may be prepared by the following methods:

/>

example 122

Analysis method

The pyridazine carboxamide derivatives exemplified above were assayed for their ability to inhibit the nav1.8 channel using one or more of the methods described below.

HEK Nav1.8β1/β2 stable expression cell line

HEK293 cell lines stably expressing human Nav1.8 (hNav1.8) ion channels with β1/β2 subunits were constructed. Cell lines are suitable for determination of IC in fluorescence and electrophysiology based assays ₅₀ . It is also suitable for the mechanisms that lead to pharmacological studies of the effect in electrophysiological analysis. At 37 ℃, 10% CO ₂ HEK293 Nav1.8 cells were grown as adherent monolayers in DMEM/high glucose medium, 10% fetal bovine serum, sodium pyruvate (2 mM), hepes (10 mM), and selection agents G418 (400 mg/L) and puromycin (0.5 mg/L).

Na _v 1.8 fluorescence inhibition assay

The compounds were made up to 10mM stock solution using DMSO as vehicle, or supplied as such stock solution. Concentration response curves were generated using a matrix multichannel pipettor. Compound source plates a 500 μm (100 x) solution in DMSO was generated by diluting 10mM compound stock in a 96 well v-bottom plate. Compounds were then serially diluted in 100% dmso to generate a 5-point 4-fold dilution regimen dose response curve. Subsequently 2 μl of 100x dose response curve was added to the pre-incubation and stimulation assay plates. 100. Mu.l of pre-incubation buffer and 200. Mu.l of stimulation buffer were then added to the plates, resulting in a final assay concentration range of 5. Mu.M to 0.02. Mu.M with a final DMSO concentration of 1%.

On the day of analysis, plates were washed with 2K EBSS buffer (135 mM NaCl, 2mM KCl, 5mM glucose, 2mM CaCl2, 1mM MgCl2, 10mM HEPES,pH 7.4) to remove cell culture medium. Sodium sensitive fluorescent dye Asante Natrium Green-2 (ANG-2) was incubated for 60min to reach equilibrium followed by washing with 2K EBSS. The plates were transferred to a fluorescent plate reader (FLIPR) ^TM Molecular Devices) for fluorescence measurements using an excitation wavelength of 490nm and an emission wavelength of 565 nm. The compounds were pre-incubated for 5 minutes in the presence of ouabain (30 μm) at the final test concentration to inhibit na+ excretion through na+/k+ exchanger. After the pre-incubation stageThe hnav1.8 channel was stimulated with 10 μm pyrethroid, mefenacet (pyrethroid deltamethrin) to prevent channel inactivation. The vehicle for analysis and 30 μm tetracaine served as negative and positive controls, respectively, for 15 minutes. The change in fluorescence peak relative to negative and positive control wells was calculated and fitted with a logistic equation to determine IC ₅₀ 。

PatchXpress Na _v 1.8 inhibition assay

HEK-Nav1.8β1/β2 cells were recorded in whole cell patch clamp using a PatchXpress automated patch clamp platform (Molecular Devices). Cell suspensions were obtained by trypsinization of the adherent monolayer followed by gentle shaking for a minimum of 30 min. Compounds were prepared from 10mM DMSO stock.

Using the one depicted in figure 1Scheme 1Nav1.8 channel variants were evaluated in which the cell voltage was initially clamped at a holding potential of-100 mV to maintain Nav1.8 in a closed resting state. After the current amplitude became stable, a series of 5 second conditioning steps were used to increasingly depolarize voltages (-100 mV to 0 mV) and the midpoint voltage for steady state inactivation was determined for each cell. The holding potential is then reset to a voltage (V _{Half of the number} Automatically set via a PatchXpress script) so that inhibition of blocked and inactivated channels can be assessed. Scheme 1 was run at a frequency of 0.1Hz until the current amplitude stabilized (automatically determined by the PatchXpress script). Custom PatchXpress stability scripts were used to monitor the effect of test reagents on Nav current amplitude, which determine the timing of compound addition and removal.

The data were processed and analyzed using a DataXpress 2.0 (Molecular Devices). Percent inhibition was calculated using microsoft Excel such that the compound blocks were normalized to the average of control and clearance currents according to the following formula = ((control + clearance)/2) -drug)/((control + clearance)/2) x 100. The normalized concentration response relationship was fitted using XLfit software (IDBS) 4 parameter logic model or sigmoid dose-response model.

hNa _V 1.8 automated patch clamp-IonFlux ^HT Analysis

The inward sodium current was recorded using an IonFlux HT automated patch clamp instrument (Fluxion Biosciences company, almeda, CA USA).

And (3) cells: HEK-293 cells were purified by human Na _V 1.8 The cDNA (type X voltage-gated sodium channel alpha subunit, accession No. NM-006514) and human beta subunit 1 (accession No. NM-001037) were stably transfected. Cells were collected with trypsin and kept in serum-free medium at room temperature, followed by recording. Cells were washed and resuspended in extracellular solution prior to application to the instrument.

Test concentration: stock solutions were prepared in DMSO at 300x final assay concentration and stored at-80 ℃ until the day of assay. On the day of analysis, aliquots of the stock solution were thawed and diluted in external solution to prepare the final test concentrations. The final concentration of 0.33% dmso was maintained for each concentration of assay compound and control.

Recording conditions: intracellular solution (mM): 100CsF, 45CsCl, 5NaCl, 10HEPES, 5EGTA (pH 7.3, titrated with 1M CsOH).

Extracellular solution (mM): 150NaCl, 4BaCl, 1MgCl ₂ 、1.8CaCl ₂ 10HEPES, 5 glucose (pH 7.4, titrated with 10M NaOH).

When the sodium channels remain at depolarized membrane potential, the channels open and deactivate and remain inactive until the membrane potential steps back to hyperpolarized membrane potential, at which point the deactivated channels revert to a closed state. Compounds that exhibited more inhibition at pulse 2 than pulse 1 were state dependent inhibitors. An example is tetracaine, which is a more effective inhibitor in the inactivated state than in the strained or open state.

The cells were held at-120 mV for 50ms, followed by a step to-10 mV for 2s to completely inactivate the sodium channel (pulse 1), and a step back to-120 mV for 10ms (to complete recovery from inactivation, whereas the inhibitor-bound channel would not recover from inactivation), followed by a step to-10 mV for 50ms (pulse 2). The scan interval was 20s (0.05 Hz). Each concentration of compound was administered for two minutes. The analysis was performed at room temperature.

Reference compound: tetracaine was used as a positive control and tested simultaneously with the test compound.

Data analysis: analysis only in the controlCurrent amplitudes exceeding 3nA at the stage. The amplitude of the sodium current was calculated by measuring the difference between the peak inward current (i.e., the current peak) and the residual current at the end of the step, which were stepped to-10 mV. Sodium current was assessed under vehicle control conditions and then at the end of each two (2) minutes of compound administration. Individual cell capture results were normalized to vehicle control amplitude and mean ± SEM calculated for each compound concentration. These values are then plotted and an estimated IC is calculated ₅₀ And (5) curve fitting.

Activity of representative Nav1.8 inhibitors

One or more of the methods described immediately above determine the ability of the representative pyridazine carboxamide derivatives exemplified above to inhibit the nav1.8 channel.

+IC ₅₀ >1μM

++IC ₅₀ 500nM-1μM

+++IC ₅₀ <500nM

Reference to the literature

All publications, patent applications, patents, and other references mentioned in this specification are indicative of the levels of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, or other reference was specifically and individually indicated to be incorporated by reference. It will be appreciated that although a number of patent applications, patents and other references are referred to herein, such references do not constitute an admission that any of these documents form part of the common general knowledge in the art.

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VI.Incorporated by reference

References and citations for other documents, such as patents, patent applications, patent publications, journals, books, papers, web site content, have been made in the present invention. All such documents are hereby incorporated by reference in their entirety for all purposes.

VII.Equivalent(s)

In addition to the various modifications and many other embodiments thereof shown and described herein, those modifications and embodiments of the invention will become apparent to those skilled in the art from the entire contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, examples and guidelines that can be adapted to practice the invention in its various embodiments and their equivalents.

Claims

1. A compound of formula (II):

wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₇ Is H, halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ A heterocyclic group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclic group or a partially unsaturated heterocyclic group, an O-aryl group having 5 or 6 members per ring, an O-heteroaryl group having 5 or 6 members per ring, an O-cycloalkyl group, an O-cycloheteroalkyl group, each optionally substituted as valency permits,

the limiting conditions are as follows:

x and Z may not both be CH; and is also provided with

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Y is NR ₈ 。

3. The compound of claim 1, wherein Y is O.

4. The compound of claim 1, wherein R ₂ Is alkyl.

5. The compound of claim 4, wherein R ₂ is-CH ₃ 。

6. The compound according to claim 1, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ Neither N nor N-O.

7. The compound according to claim 1, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ One of them is N or N-O.

8. The compound according to claim 1, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ And both are N or N-O.

9. The compound of claim 1, wherein Z is CH.

10. The compound of claim 1, wherein Z is N.

11. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of formula (II):

wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₈ h, C of a shape of H, C _1-3 Alkyl or C _3-5 A cycloalkyl group,

the limiting conditions are as follows:

x and Z may not both be CH; and is also provided with

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein Y is NR ₈ 。

13. The method of claim 11, wherein Y is O.

14. The method of claim 11, wherein R ₂ Is alkyl.

15. The method of claim 14, wherein R ₂ is-CH ₃ 。

16. The method of claim 11, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ Neither N nor N-O.

17. The method of claim 11, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ One of them is N or N-O.

18. The method of claim 11, wherein J ₁ 、J ₂ 、J ₃ 、J ₄ And J ₅ And both are N or N-O.

19. The method of claim 11, wherein Z is CH.

20. The method of claim 11, wherein Z is N.

21. A compound of formula (III):

wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

z is CH, N or N-O,

R ₇ is-H, halogen, -CD ₃ Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, -CF ₃ 、-OCF ₃ A carbocyclyl group having 3 to 6 members per ring, a heterocyclyl group having 5 or 6 members per ring, a heteroaryl group having 5 or 6 ring members, a saturated heterocyclyl group having 3 to 6 members per ring, or a partially unsaturated heterocyclyl group, an O-aryl group having 5 or 6 members per ring, an O-heteroaryl group having 5 or 6 members per ring, an O-cycloalkyl group, an O-cycloheteroalkyl group, each optionally substituted as valency permits,

R ₁₀ And R is ₁₁ Each of which is independently selected from-H and C _1-5 Alkyl, or R ₁₀ And R is ₁₁ Together with the nitrogen atom to which it is attached, form a heterocyclic group having 3 to 6 members, wherein the C _1-5 Alkyl and heterocyclyl are each optionally substituted where the valency permits,

the limiting conditions are as follows:

J ₁ 、J ₂ 、J ₃ 、J ₄ and J ₅ Not more than two of them are N or N-O；

W ₁ 、W ₂ 、W ₃ 、W ₄ And W is ₅ Not more than two of them are N;

X and Z may not both be CH,

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein W ₃ Is CR (CR) ₉ 。

23. The compound of claim 22, wherein R ₉ is-C (O) NH ₂ 。

24. The compound of claim 21, wherein W ₃ Is N.

25. The compound of claim 21, wherein W ₂ Is CH and W ₄ Is CR (CR) ₉ 。

26. The compound of claim 25, wherein R ₉ is-C (O) NH ₂ 。

27. The compound of claim 21, wherein W ₂ And W is ₄ Are all CR ₉ 。

28. The compound of claim 27, wherein W ₂ Is C-C (O) NH ₂ And W is ₄ Is C-S (O) ₂ CH ₃ 。

29. The compound of claim 21, wherein X and Z are both N.

30. The compound of claim 21, wherein the compound is selected from the group consisting of formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and (III-8):

31. Na (Na) _V 1.8 inhibitors of sodium channels having the structure of formula (III):

wherein:

J ₃ For N, N-O or CR ₇ ；

X is CH or N;

z is CH, N or N-O,

R ₉ each of (3)Examples are independently-C (O) NR ₁₀ R ₁₁ 、-S(O) ₂ C _1-6 Alkyl, -S (O) (NH) C _1-6 Alkyl, C _1-3 Alkyl or C _3-5 Cycloalkyl; and is also provided with

the limiting conditions are as follows:

W ₁ 、W ₂ 、W ₃ 、W ₄ and W is ₅ Not more than two of them are N;

X and Z may not both be CH,

or a pharmaceutically acceptable salt thereof.

32. The inhibitor according to claim 31, wherein W ₃ Is CR (CR) ₉ 。

33. The inhibitor according to claim 32, wherein R ₉ is-C (O) NH ₂ 。

34. The inhibitor according to claim 31, wherein W ₃ Is N.

35. The inhibitor according to claim 31, wherein W ₂ Is CH and W ₄ Is CR (CR) ₉ 。

36. The inhibitor according to claim 35, wherein R ₉ is-C (O) NH ₂ 。

37. The inhibitor according to claim 31, wherein W ₂ And W is ₄ Are all CR ₉ 。

38. The inhibitor according to claim 37, wherein W ₂ Is C-C (O) NH ₂ And W is ₄ Is C-S (O) ₂ CH ₃ 。

39. The inhibitor according to claim 31, wherein X and Z are both N.

40. The inhibitor of claim 31, wherein the inhibitor is represented by a structure selected from the group consisting of formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and (III-8):

41. a compound of formula (I):

wherein:

R ₁ is-CN or-CF ₃ ；

R ₃ Is halogen, alkyl, alkoxy or-CD ₃ ；

R ₅ Is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, CF ₃ 、OCF ₃ A fused heterocyclyl having 5 or 6 members per ring, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl or a partially unsaturated heterocyclyl, each optionally substituted where the valency permits;

e is CH or CF;

x is CH or N;

z is CH or N; and is also provided with

-CD ₃ In order to have a completely deuterated methyl group,

provided that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

42. The compound of claim 41, wherein R ₁ is-CN.

43. A compound according to claim 42, wherein R ₁ is-CF ₃ 。

44. The compound of claim 41, wherein R ₃ Is halogen.

45. The compound of claim 41, wherein R ₃ Is alkyl.

46. The compound of claim 41, wherein R ₃ Is an alkoxy group.

47. The compound of claim 41 wherein E is CH.

48. The compound of claim 41 wherein E is CF.

49. The compound of claim 41 wherein Z is CH.

50. The compound of claim 41 wherein Z is N.

51. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of formula (I):

wherein:

R ₁ is-CN or-CF ₃ ；

R ₃ Is halogen, alkyl, alkoxy or-CD ₃ ；

e is CH or CF;

x is CH or N;

z is CH or N; and is also provided with

-CD ₃ In order to have a completely deuterated methyl group,

provided that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein R is ₁ is-CN.

53. The method of claim 52, wherein R is ₁ is-CF ₃ 。

54. The method of claim 51, wherein R is ₃ Is halogen.

55. The method of claim 51, wherein R is ₃ Is alkyl.

56. The method of claim 51, wherein R is ₃ Is an alkoxy group.

57. The method of claim 51, wherein E is CH.

58. The method of claim 51, wherein E is CF.

59. The method of claim 51, wherein Z is CH.

60. The method of claim 51, wherein Z is N.

61. A compound of formula (I):

wherein:

the aryl, heteroaryl, and unsaturated heterocyclyl are each optionally fused to one selected from the group consisting of: an optionally saturated carbocyclyl group containing 5 to 6 ring members and an optionally saturated heterocyclyl group containing 5 to 6 ring members and 1 to 3 heteroatoms;

the aryl, heteroaryl, and unsaturated heterocyclyl are each optionally substituted with one or more groups selected from the group consisting of: - (CH) ₂ ) _n NR ^e C(O)N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e C(O)NR ^e R ^j 、-(CH ₂ ) _n NR ^e C(O)OR ^j 、-(CH ₂ ) _n NR ^e C(O)R ^j 、-(CH ₂ ) _n NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m R ^j Alkyl iminothiolonyl, alkyl sulfinyl, alkyl sulfonamide, alkyl sulfonyl, alkyl sulfoxide, alkyl sulfonimide, alkyl sulfide, amino, aryl, arylalkoxy, aryloxy, -C (O) NH ₂ 、-C(O)NR ^e R ^j 、-C(O)R ^j 、C ₁ -C ₄ Alkoxy, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ Cycloalkyl, -CF ₃ 、-CN、-CO ₂ H、-CO ₂ R ^j Cyano, -H, halogen, heteroaryl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihaloalkoxy, morpholino, nitro, O-aryl, -OC (O) N (R) ^j ) ₂ 、-OC(O)NR ^e R ^j 、-OC(O)R ^j 、-OC ₁ -C ₆ Alkyl, -OC ₂ -C ₆ Alkenyl, -OC ₂ -C ₆ Cycloheteroalkyl, -OC ₃ -C ₆ Cycloalkyl, -OH, O-heteroaryl, oxazolyl, oxo, -S (O) ₂ R ^j 、-SO ₂ Aryl, -SO ₂ C ₁ -C ₆ Alkenyl, -SO ₂ C ₁ -C ₆ Alkyl, -SO ₂ C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ C ₃ -C ₆ Cycloalkyl, SO ₂ Heteroaryl, -SO ₂ NH ₂ 、-SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C ₂ -C ₆ Alkenyl, -SO ₂ NR ^e C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H、-SR ^j Sulphoxide imino-S (O) (=nr ^a )R ^a sulfonylamidine-S (O) (=nr ^a )N(R ^a ) ₂ Sulfonimidyl fluoride-S (O) (=nr ^a ) F and sulfonyldiimine-S (=nr ^a ) ₂ R ^a Wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl) and-N (C) ₁ -C ₆ Alkyl group ₂ ；

Each heteroatom in the heteroaryl, unsaturated heterocyclyl and optionally saturated heterocyclyl is independently O, S or N (R ^h ) _q Each may be in its oxidized or unoxidized state;

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

each R ^j Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, C ₂ -C ₆ Cycloheteroalkyl, arylA radical or heteroaryl, wherein R ^j Optionally substituted with one or more substituents independently selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, -OH, -OC ₁ -C ₆ Alkyl, -OC ₃ -C ₆ Cycloalkyl, halogen, cyano and-S (O) ₂ CH ₃ ；

e is CH, CF or N;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N, N ⁺ O ^- Or CH;

each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

62. The compound of claim 61, wherein R ₂ Is an optionally substituted aryl group.

63. The compound of claim 61, wherein R ₂ Is optionally substituted heteroaryl.

64. The compound of claim 61, wherein R ₂ Is an optionally substituted unsaturated heterocyclyl group.

65. The compound of claim 61, wherein R ₁ Is halogen.

66. The compound of claim 61, wherein R ₁ Is C ₁ -C ₃ An alkyl group.

67. The compound of claim 61, wherein R ₁ Is C ₃ -C ₄ Cycloalkyl groups.

68. The compound of claim 61, wherein R ₁ Is haloalkyl.

69. The compound of claim 61, wherein R ₁ Is halogenated cycloalkyl.

70. The compound of claim 61, wherein R ₁ H.

71. The compound of claim 61, wherein R ₃ Is mono-, di-or tri-halogenated C ₁ -C ₄ An alkyl group.

72. The compound of claim 61, wherein R ₃ is-CF ₃ 。

73. The compound of claim 61, wherein E is CH or CF.

74. The compound of claim 61, wherein E is N.

75. The compound of claim 61, wherein Q is CH or CF.

76. The compound of claim 61, wherein Q is N.

77. The compound of claim 61, wherein T is CH or CF.

78. The compound of claim 61, wherein T is N.

79. The compound of claim 61, wherein W is CH or CF.

80. The compound of claim 61, wherein W is N.

81. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of formula (I):

wherein:

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

e is CH or CF;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N or N ⁺ O ^- ；

Z is N or N ⁺ O ^- ，

Each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

82. The method of claim 81, wherein R ₂ Is an optionally substituted aryl group.

83. The method of claim 81, wherein R ₂ Is optionally substituted heteroaryl.

84. The method of claim 81, wherein R ₂ Is an optionally substituted unsaturated heterocyclyl group.

85. The method of claim 81, wherein R ₁ Is halogen.

86. The method of claim 81, wherein R ₁ Is C ₁ -C ₃ An alkyl group.

87. The method of claim 81, wherein R ₁ Is C ₃ -C ₄ Cycloalkyl groups.

88. The method of claim 81, wherein R ₁ Is haloalkyl.

89. The method of claim 81, wherein R ₁ Is halogenated cycloalkyl.

90. The method of claim 81, wherein R ₁ H.

91. The method of claim 81, wherein R ₃ Is mono-, di-or tri-halogenated C ₁ -C ₄ An alkyl group.

92. The method of claim 81, wherein R ₃ is-CF ₃ 。

93. The method of claim 81, wherein E is CH or CF.

94. The method of claim 81, wherein E is N.

95. The method of claim 81, wherein Q is CH or CF.

96. The method of claim 81, wherein Q is N.

97. The method of claim 81, wherein T is CH or CF.

98. The method of claim 81, wherein T is N.

99. The method of claim 81, wherein W is CH or CF.

100. The method of claim 81, wherein W is N.

101. The method of claim 81, wherein the condition is selected from the group consisting of: abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itching, acute pain with severe trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, idiopathic reactions, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn, oral glowing syndrome, calcium pyrophosphate deposition disease, cervicales headache, charceis neurogenic osteoarthropathy (Charcot neuropathic osteoarthropathy), chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic lower back pain, chronic pancreatitis, chronic post-traumatic headache, chronic extensive pain, cluster headache, complex regional pain syndrome sustained unilateral facial pain with additional episodes, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic hyperosteogeny, intervertebral disc degenerative pain, ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, fabry's disease, facet joint syndrome, lumbar surgical failure (failed back surgery) syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngalgia, glossopharyngeal neuropathy pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythema limb pain, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, pain associated with lumbar surgery, limb bone striated hypertrophy, migraine, multiple sclerosis, musculoskeletal injury, myofascial oral facial pain, post-ischemic neurodegeneration, type II neurofibromatosis, neuropathic eye pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, oral facial pain, osteoarthritis, overactive bladder, congenital thick nail disease, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful arthroplasty, pancreatitis, parkinson's disease, paroxysmal extreme pain, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic facial pain, phantom limb pain rheumatalgia, postherpetic neuralgia, mastectomy pain syndrome, postoperative pain, post-stroke pain, postoperative pain, thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiation-induced peripheral neuropathy, raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, idiopathic pain, stump pain, subacute cough, temporomandibular joint disease, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvar pain, and cervical whiplash.

102. The method of claim 101, wherein the condition is selected from the group consisting of: abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, severe traumatic/injury acute pain, ankylosing spondylitis, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, oral glowing syndrome, calcium pyrophosphate deposition disease, cervicales headache, shakovic's neuro osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic lower back pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, sustained unilateral facial pain with additional episodes, toothache, complex regional pain syndrome, diabetic peripheral neuropathy, diffuse idiopathic hyperosteogeny, intervertebral disc degeneration pain, eiles-holos syndrome, endometriosis, epidermolysis bullosa, erythromelalgia Fabry disease, facet joint syndrome, lumbar surgery failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, limb bone striated hypertrophy, migraine, multiple sclerosis, myofascial orofacial pain, type II neurofibroma, neuropathic ophthalmalgia, neuropathic pain, nociceptive pain, non-cardiac chest pain, oral mucosal pain, orofacial pain, osteoarthritis, congenital pachyrhisis, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful arthroplasty, parkinson's disease, paroxysmal extreme pain, pemphigus, perioperative pain, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, polymyalgia rheumatica, post mastectomy pain syndrome, post operative pain, post stroke pain, post operative pain, postthoracic pain syndrome, post traumatic stress disorder, pre operative pain, psoriasis, psoriatic arthritis, pudendum neuralgia, pyoderma gangrenosum, radiation-induced peripheral neuropathy, raynaud's disease, renal colic, rheumatoid arthritis, salivary gland pain, sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, temporomandibular joint disease, tension-type headache, vascular leg ulcers, vulvar pain, and cervical whiplash.

103. The method of claim 101, wherein the condition is selected from the group consisting of: acute itch, allergic dermatitis, chronic itch, contact dermatitis, itch and pruritus.

104. The method of claim 101, wherein the condition is selected from the group consisting of: acute cough, chronic cough, and subacute cough.

105. A compound of formula (I):

wherein:

R ₂ selected from the group consisting of: cycloalkyl having 4 to 6 ring members, cycloheteroalkyl having 5 to 6 ring members, spirocycloalkyl having 5 to 14 ring members and spiroheteroalkyl having 5 to 14 ring members, wherein:

the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spiroheterocycloalkyl are each optionally fused to one selected from the group consisting of: an optionally saturated carbocyclyl group containing 5 to 6 ring members and an optionally saturated heterocyclyl group containing 5 to 6 ring members and 1 to 3 heteroatoms;

the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spirocycloheteroalkyl are each optionally substituted with one or more groups selected from the group consisting of: - (CH) ₂ ) _n NR ^e C(O)N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e C(O)NR ^e R ^j 、-(CH ₂ ) _n NR ^e C(O)OR ^j 、-(CH ₂ ) _n NR ^e C(O)R ^j 、-(CH ₂ ) _n NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ 、-(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j 、-(CH ₂ ) _n NR ^e S(O) _m R ^j Alkyl iminothiolonyl, alkyl sulfinyl, alkyl sulfonamide, alkyl sulfonyl, alkyl sulfoxide, alkyl sulfonimide, alkyl sulfide, amino, aryl, arylalkoxy, aryloxy, -C (O) NH ₂ 、-C(O)NR ^e R ^j 、-C(O)R ^j 、C ₁ -C ₄ Alkoxy, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ Cycloalkyl, -CF ₃ 、-CN、-CO ₂ H、-CO ₂ R ^j Cyano, -H, halogen, heteroaryl, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo or trihaloalkoxy, morpholino, nitro, O-aryl, -OC (O) N (R) ^j ) ₂ 、-OC(O)NR ^e R ^j 、-OC(O)R ^j 、-OC ₁ -C ₆ Alkyl, -OC ₂ -C ₆ Alkenyl, -OC ₂ -C ₆ Cycloheteroalkyl, -OC ₃ -C ₆ Cycloalkyl, -OH, O-heteroaryl, oxazolyl, oxo, -S (O) ₂ R ^j 、-SO ₂ Aryl, -SO ₂ C ₁ -C ₆ Alkenyl, -SO ₂ C ₁ -C ₆ Alkyl, -SO ₂ C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ C ₃ -C ₆ Cycloalkyl, SO ₂ Heteroaryl, -SO ₂ NH ₂ 、-SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ Alkyl, -SO ₂ NR ^e C ₂ -C ₆ Alkenyl, -SO ₂ NR ^e C ₂ -C ₆ Cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ Cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H、-SR ^j Sulfonyl-S (O) (=nr) ^a )R ^a sulfonylamidine-S (O) (=nr ^a )N(R ^a ) ₂ Sulfonimidyl fluoride-S (O) (=nr ^a ) F, sulfonyldiimine-S (=nr ^a ) ₂ R ^a And R is ^k R ^l Wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH ₂ 、-NH(C ₁ -C ₆ Alkyl) and-N (C) ₁ -C ₆ Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Each heteroatom in the cycloheteroalkyl, spirocyclic heteroalkyl and optionally saturated heterocyclyl is independently O, S or N (R ^h ) _q Each may be in its oxidized or unoxidized state;

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

each R ^j Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, C ₂ -C ₆ A cycloheteroalkyl group,Aryl or heteroaryl, wherein R ^j Optionally substituted with one or more substituents independently selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, -OH, -OC ₁ -C ₆ Alkyl, -OC ₃ -C ₆ Cycloalkyl, halogen, cyano and-S (O) ₂ CH ₃ ；

E is CH or CF;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N or N ⁺ O ^- ，

Each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

106. The compound of claim 105, wherein R ₂ Is optionally substituted cycloalkyl.

107. The compound of claim 105, wherein R ₂ Is optionally substituted cycloheteroalkyl.

108. The compound of claim 105, wherein R ₂ Is an optionally substituted spirocycloalkyl group.

109. The compound of claim 105, wherein R ₂ Is optionally substituted spirocycloalkyl.

110. The compound of claim 105, wherein R ₁ Is halogen.

111. The compound of claim 105, wherein R ₁ Is C ₁ -C ₃ An alkyl group.

112. The compound of claim 105, wherein R ₁ Is C ₃ -C ₄ Cycloalkyl groups.

113. The compound of claim 105, wherein R ₁ Is haloalkyl.

114. The compound of claim 105, wherein R ₁ Is halogenated cycloalkyl.

115. The compound of claim 105, wherein R ₁ H.

116. The compound of claim 105, wherein R ₃ is-CF ₃ 。

117. The compound of claim 105, wherein E is CH or CF.

118. The compound of claim 105, wherein E is N.

119. The compound of claim 105, wherein Q is CH or CF.

120. The compound of claim 105, wherein Q is N.

121. The compound of claim 105, wherein T is CH or CF.

122. The compound of claim 105, wherein T is N.

123. The compound of claim 105, wherein W is CH or CF.

124. The compound of claim 105, wherein W is N.

125. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of formula (I):

wherein:

each R ^e independently-H, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups;

each R ^h independently-H or C ₁ -C ₆ An alkyl group;

each R ^j Independently and separatelyIs C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₆ Cycloalkyl, C ₂ -C ₆ Cycloheteroalkyl, aryl or heteroaryl, wherein R is ^j Optionally substituted with one or more substituents independently selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, -OH, -OC ₁ -C ₆ Alkyl, -OC ₃ -C ₆ Cycloalkyl, halogen, cyano and-S (O) ₂ CH ₃ ；

e is CH or CF;

q is CH, CF or N;

t is CH, CF or N;

w is CH, CF or N;

x is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

y is N or N ⁺ O ^- ；

Z is N or N ⁺ O ^- ，

Each m is independently 0-2;

each n is independently 0-4; and is also provided with

Each q is independently 0 or 1,

or a pharmaceutically acceptable salt thereof.

126. The method of claim 125, wherein R ₂ Is optionally substituted cycloalkyl.

127. The method of claim 125, wherein R ₂ Is optionally substituted cycloheteroalkyl.

128. The method of claim 125, wherein R ₂ Is an optionally substituted spirocycloalkyl group.

129. The method of claim 125, wherein R ₂ Is optionally substituted spirocycloalkyl.

130. The method of claim 125, wherein R ₁ Is halogen.

131. The method of claim 125, wherein R ₁ Is C ₁ -C ₃ An alkyl group.

132. The method of claim 125, wherein R ₁ Is C ₃ -C ₄ Cycloalkyl groups.

133. The method of claim 125, wherein R ₁ Is haloalkyl.

134. The method of claim 125, wherein R ₁ Is halogenated cycloalkyl.

135. The method of claim 125, wherein R ₁ H.

136. The method of claim 125, wherein R ₃ is-CF ₃ 。

137. The method of claim 125, wherein E is CH or CF.

138. The method of claim 125, wherein E is N.

139. The method of claim 125, wherein Q is CH or CF.

140. The method of claim 125, wherein Q is N.

141. The method of claim 125, wherein T is CH or CF.

142. The method of claim 125, wherein T is N.

143. The method of claim 125, wherein W is CH or CF.

144. The method of claim 125, wherein W is N.

145. The method of claim 125, wherein the condition is selected from the group consisting of: abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itching, acute pain with severe trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, idiopathic reactions, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burns, oral glowing syndrome, calcium pyrophosphate deposition disease, cervical headache, charcol's neuro-osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic low back pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, continuous unilateral facial pain with additional episodes, contact dermatitis, cough, toothache, dental pain diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic hyperostosis, intervertebral disc degenerative pain, eilles-go syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromatous limb pain, fabry disease, facet joint syndrome, lumbar surgical failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathy pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, limb bone striated hypertrophy, migraine, multiple sclerosis, musculoskeletal injury, myofascial facial pain, post-ischemic neurodegeneration, type II neurofibromatosis, neuropathic eye pain, neuropathic pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, post-inflammatory arthritis, mastocytosis, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, overactive bladder, congenital pachymia, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful arthroplasty, pancreatitis, parkinson's disease, paroxysmal extreme pain, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, polymyalgia rheumatica, post herpetic neuralgia, post-mastectomy pain syndrome, post-operative pain post-stroke pain, post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritis, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiation-induced peripheral neuropathy, raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, idiopathic pain, stump pain, subacute cough, temporomandibular joint disease, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and neck whiplash.

146. The method of claim 145, wherein the condition is selected from the group consisting of: abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, severe traumatic/injury acute pain, ankylosing spondylitis, behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, oral glowing syndrome, calcium pyrophosphate deposition disease, cervicales headache, shakovic's neuro osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic lower back pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, sustained unilateral facial pain with additional episodes, toothache, complex regional pain syndrome, diabetic peripheral neuropathy, diffuse idiopathic hyperosteogeny, intervertebral disc degeneration pain, eiles-holos syndrome, endometriosis, epidermolysis bullosa, erythromelalgia Fabry disease, facet joint syndrome, lumbar surgery failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, limb bone striated hypertrophy, migraine, multiple sclerosis, myofascial orofacial pain, type II neurofibroma, neuropathic ophthalmalgia, neuropathic pain, nociceptive pain, non-cardiac chest pain, oral mucosal pain, orofacial pain, osteoarthritis, congenital pachyrhisis, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful arthroplasty, parkinson's disease, paroxysmal extreme pain, pemphigus, perioperative pain, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, polymyalgia rheumatica, post mastectomy pain syndrome, post operative pain, post stroke pain, post operative pain, postthoracic pain syndrome, post traumatic stress disorder, pre operative pain, psoriasis, psoriatic arthritis, pudendum neuralgia, pyoderma gangrenosum, radiation-induced peripheral neuropathy, raynaud's disease, renal colic, rheumatoid arthritis, salivary gland pain, sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, temporomandibular joint disease, tension-type headache, vascular leg ulcers, vulvar pain, and cervical whiplash.

147. The method of claim 145, wherein the condition is selected from the group consisting of: acute itch, allergic dermatitis, chronic itch, contact dermatitis, itch and pruritus.

148. The method of claim 145, wherein the condition is selected from the group consisting of: acute cough, chronic cough, and subacute cough.

149. A compound of formula (I):

wherein:

R ₃ selected from the group consisting of: hydrogen, cyano, halogen, C ₁ -C ₈ Alkoxy, monohalo, dihalo and trihalo C ₁ -C ₄ Alkyl, monohalo, dihalo and trihaloC ₁ -C ₄ Alkoxy, substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₃ -C ₈ Cycloalkyl, -NO ₂ ；

and pharmaceutically acceptable salts thereof.

150. A compound according to claim 149, wherein:

R ₁ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with one or more groups selected from the group consisting of: substituted or unsubstituted C ₁ -C ₈ An alkyl group; halogen; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1,2,3, 4, 5, 6, 7 and 8; -S-CF ₃ ；

R ₂ Selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl, wherein said phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridin-1-oxide, 1,2, 3-thiadiazolyl, 1,2, 4-triazolyl and 1, 3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of: unsubstituted or substituted C ₁ -C ₈ An alkyl group; halogen; cyano group; an oxo group; -O-R ₅ Which is provided withR in (B) ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ and-CHF ₂ A group of groups; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1,2,3, 4, 5, 6, 7 and 8; -NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; morpholinyl; oxazolyl; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl, and R ₁₁ Is C ₁ -C ₄ Alkyl, provided that when Y is nitrogen and R ₂ R in the case of phenyl or pyridyl ₈ Not being-NR ₆ R ₇ ；

151. The compound of claim 149, wherein the compound is of formula (II):

wherein:

R ₃ And R is R ₄ Together form a mixture comprising R ₃ And R is R ₄ Attached carbon atomsSon C ₃ -C ₅ A carbocycle;

n is an integer selected from 0, 1, 2, 3, 4 and 5;

152. The compound of claim 151, wherein R ₂ Selected from the group consisting of:

wherein:

m is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

R ₂₅ selected from the group consisting of: h is formed; morpholinyl; oxazolyl; halogen; cyano group; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Wherein each R is ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl, and R ₁₁ Is C ₁ -C ₄ Alkyl, provided that when Y is nitrogen and R ₂ R in the case of phenyl or pyridyl ₈ Not being-NR ₆ R ₇ ；

R ₂₆ Halogen or cyano;

Each R ₂₈ Independently H or C ₁ -C ₄ An alkyl group.

153. The compound of claim 151, wherein the compound is of formula (II-a):

wherein:

R ₂ selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted with a substituent selected from the group consisting of: unsubstituted or substituted C ₁ -C ₈ An alkyl group; halogen; cyano group; an oxo group; a heterocycloalkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CH ₂ F and-CHF ₂ A group of groups; - (CH) ₂ ) _q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; morpholinyl; oxazolyl; -C (=o) -R ₈ Wherein R is ₈ Selected from the group consisting of-NR ₆ R ₇ And C ₁ -C ₄ Alkyl, wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; -S (=o) -R ₉ ；-S(＝O) ₂ -R ₉ ；-S(＝O)(＝NR ₁₀ )-R ₁₁ The method comprises the steps of carrying out a first treatment on the surface of the And-n=s (=o) - (R ₁₁ ) ₂ Each of which isR is a number of ₉ Independently C ₁ -C ₄ Alkyl, -CF ₃ or-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl group, R ₁₀ Is H or C ₁ -C ₄ Alkyl, and R ₁₁ Is C ₁ -C ₄ An alkyl group;

154. The compound of claim 153, wherein the aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridinyl N-oxide, pyridazinyl, and pyrimidinyl.

155. The compound of claim 154, wherein R ₂ Selected from the group consisting of: (trifluoromethanesulfonyl) phenyl, 1,2, 4-triazolyl, 1, 3-benzothiazol-2-yl, 1, 3-benzothiazol-6-yl, 2-fluoro-5-methylsulfonylphenyl, 2-methoxy-4-pyridinyl, 2-methyl-4-pyridinyl, 3- (dimethylsulfamoyl) phenyl, 3- (methylsulfinylphenyl), 3- (N, S-dimethylsulfamoyl) phenyl, 3-carbamoylphenyl, 3-cyanophenyl, 3-dimethylsulfamoylphenyl, 3-methylsulfinylphenyl, 3-morpholinophenyl, 3-oxazol-5-ylphenyl, 3-pyridinyl, 4-cyanophenyl, 4-pyridinyl, 6-cyano-3-pyridinyl, 6-methyl-3-pyridinyl, dimethyl (oxo) - λ6-sulfinyl]Amino group]Phenyl, pyrazolyl, pyridazin-4-yl, pyridazinyl, pyridin-4-yl, pyridinyl, pyrimidin-4-yl, pyrimidinyl and thiadiazolyl.

156. The compound of claim 149, wherein the compound is of formula (III):

wherein:

R ₂ selected from the group consisting of:

and is also provided with

R ₃ And R is ₄ Is H or-CF ₃ Provided that if R ₃ Is H, then R ₄ is-CF ₃ And if R ₄ Is H, then R ₃ is-CF ₃ 。

157. The compound of claim 156, wherein the compound is of formula (III-a):

wherein:

R ₁ selected from the group consisting of phenyl, pyridyl and 1, 3-benzothiazol-4-ylA group, wherein the phenyl and pyridyl groups may be unsubstituted or substituted with one or more of: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; and is also provided with

158. The compound of claim 157, wherein R ₁ Selected from the group consisting of: 2, 4-dichlorophenyl group, 4-difluoromethoxyphenyl group and 2-chloro-4-methoxyphenyl group.

159. The compound of claim 156, wherein the compound is of formula (III-b):

wherein:

160. The compound of claim 156, wherein the compound is of formula (III-c):

wherein:

R ₁ is halogen, C ₁ -C ₈ Alkyl, -O-R ₅ Phenyl substituted by one or more of (a) wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3,4, 5, 6, 7 and 8.

161. The compound of claim 160, wherein R ₁ Selected from the group consisting of: 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2, 4-dimethoxyphenyl, 2, 4-difluorophenyl and 3, 4-difluorophenyl.

162. The compound of claim 156, wherein the compound is of formula (III-d):

wherein:

R ₁ selected from the group consisting of phenyl, pyridyl and 1, 3-benzothiazol-4-yl, wherein said phenyl and pyridineThe groups may be unsubstituted or substituted with one or more of the following: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ Wherein R is ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; and is also provided with

163. The compound of claim 162, wherein the compound is of formula (III-d'):

164. The compound of claim 156, wherein the compound is of formula (III-e):

wherein:

R ₁ selected from the group consisting of phenyl, pyridinyl, and 1, 3-benzothiazol-4-yl, wherein the phenyl and pyridinyl may be unsubstituted or substituted with one or more of: halogen; c (C) ₁ -C ₈ An alkyl group; -O-R ₅ WhereinR ₅ Selected from C ₁ -C ₈ Alkyl, -CF ₃ 、-CHF ₂ And- (CH) ₂ ) _p -CF ₃ Wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF ₃ ；-NR ₆ R ₇ Wherein R is ₆ And R is ₇ Selected from H and C ₁ -C ₄ Alkyl groups; and is also provided with

165. The compound of claim 164, wherein the compound is of formula (III-e'):

166. The compound of claim 156, wherein the compound is of formula (III-f):

wherein:

167. The compound of claim 166, wherein the compound is of formula (III-f'):

wherein:

r1 is selected from the group consisting of: 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2, 4-difluorophenyl, 4-difluoromethoxyphenyl, 2, 4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3, 4-difluorophenyl and 2-chloro-4-fluorophenyl.

168. The compound of claim 156, wherein the compound is of formula (III-g):

wherein:

R ₂ Selected from the group consisting of:

169. the compound of claim 168, wherein R ₁ Selected from the group consisting of:

/>

170. the compound of claim 168, wherein the compound of formula (III-g) is selected from the group consisting of:

171. The compound of claim 149, wherein the compound is of formula (IV):

wherein:

R ₂ selected from the group consisting of:

()wherein R is _2b Selected from the group consisting of H, C ₁ -C ₄ Alkyl and halogen; and R is ₁₄ Is C ₁ -C ₄ An alkyl group;

(iii)wherein R is _5b' Selected from H, halogen and C ₁ -C ₄ Alkyl groups; />

(iv)Wherein R is _4b Is H or halogen;

(v)wherein R is ₉ Is H or C ₁ -C ₄ An alkyl group; and

(vi)

172. the compound of claim 171, wherein the compound is of formula (IV-a):

173. the compound of claim 172, wherein R ₂ Selected from the group consisting of:

174. the compound of claim 172, wherein the compound of formula (IV-a) is selected from the group consisting of:

175. The compound of claim 171, wherein the compound is of formula (IV-b):

wherein:

R ₃ and R is ₄ Is H or-CF ₃ Provided that if R ₃ Is H, then R ₄ is-CF ₃ And if R ₄ Is H, then R ₃ is-CF ₃ ；

R ₁₄ is C ₁ -C ₄ An alkyl group; and is also provided with

176. The compound of claim 175, wherein R ₁ Selected from the group consisting of: phenyl, 4-fluorophenyl, 2, 4-dichlorophenyl, 2, 4-dimethylphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, Difluoromethoxy phenyl, 3-fluoro-4-trifluoromethoxy phenyl, 3-fluorophenyl, 2, 5-difluorophenyl, 4-methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3, 4-difluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, 4- (2, 2-trifluoroethoxy) phenyl, 4- (trifluoromethylthio) phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2, 4-dimethoxyphenyl, 3,4, 5-trifluorophenyl, 3, 5-dichlorophenyl, 6-trifluoromethyl-3-pyridinyl, 1, 3-benzothiazol-4-yl, 4-difluoromethoxy phenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl.

177. The compound of claim 171, wherein the compound is of formula (IV-c):

wherein:

R ₁ is thatWherein:

pharmaceutically acceptable salts thereof.

178. The compound of claim 177, wherein:

(i)R _4a is halogen; r is R _2a Selected from the group consisting of H, C ₁ -C ₄ Alkyl, halogenAnd C ₁ -C ₄ Alkoxy groups; r is R _3a Is H or halogen; r is R _5a Is H or halogen; and R is _6a Is H;

(ii)R _2a and R is _4a Each is C ₁ -C ₄ An alkoxy group;

179. The compound of claim 178, wherein R ₁ Selected from the group consisting of:

180. the compound of claim 177, wherein the compound of formula (IV-c) is selected from the group consisting of:

181. The compound of claim 171, wherein the compound is of formula (IV-d):

wherein:

R ₁ is thatWherein:

pharmaceutically acceptable salts thereof.

182. A compound according to claim 181, wherein:

(ii)R _2a and R is _4a Each is C ₁ -C ₄ An alkoxy group;

(iii)R _4a is-OF ₃ ；R _2a Selected from H, halogenElement and C ₁ -C ₄ Alkyl groups; r is R _3a And R is _6a Each is H; r is R _5a Is H or halogen;

183. The compound of claim 182, wherein R ₁ Selected from the group consisting of:

184. the compound of claim 181, wherein the compound of formula (IV-d) is selected from the group consisting of:

185. The compound of claim 171, wherein the compound is of formula (IV-e):

wherein:

R ₄ Selected from H and branched or straight chain C ₁ -C ₄ Alkyl groups.

186. The compound of claim 185, wherein the compound of formula (IV-e) is selected from the group consisting of:

3- (2-chloro-4-fluorophenoxy) -N- (3- (S-methanesulfonyl) phenyl) -6- (pentafluoro-lambda) ⁶ -sulfanyl) pyridazine-4-carboxamide.

187. The compound of claim 171, wherein the compound is of formula (IV-f):

wherein:

R ₁ is thatWherein:

188. A compound according to claim 187, wherein:

189. The compound of claim 187, wherein R ₁ Selected from the group consisting of:

190. the compound of claim 187, wherein the compound of formula (IV-f) is selected from the group consisting of:

191. The compound of claim 171, wherein the compound is of formula (IV-g):

wherein:

R ₂₀ is C ₁ -C ₄ An alkyl group; and is also provided with

R ₂₁ Is H or C ₁ -C ₄ An alkyl group.

192. Used for adjusting Na _v 1.8 sodium ion channel, comprising administering to a subject in need thereof a modulating effective amount of any one of claims 149-191Compounds of formula (I-VI).

193. A composition for inhibiting Na _v 1.8 comprising administering to a subject in need thereof an effective inhibitory amount of a compound of formula (I-VI) according to any one of claims 149-191.

194. A method for treating and/or reducing Na _v 1.8 a method of increasing activity or expression of symptoms of a related condition, disease or disorder, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I-VI) according to any one of claims 149-191 to treat and/or reduce symptoms of the condition, disease or disorder.

195. The method of claim 194, wherein the and Na _v 1.8 an increased activity or expression associated condition, disease or disorder selected from the group consisting of: pain, respiratory disease, neurological and psychiatric disorders, and combinations thereof.

196. The method of claim 195, wherein the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, paroxysmal pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury and combinations thereof.

197. The method of claim 194, wherein the disease or condition is selected from the group consisting of: HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, multiple Sclerosis (MS), amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, narcolepsy, myasthenia syndrome, myotonic, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, local and systemic tonic seizures, restless leg syndrome, cardiac arrhythmias, fibromyalgia, neuroprotection under ischemia due to stroke or nerve trauma, tachycardia, atrial fibrillation, and praise (Pitt Hopkins Syndrome, PTHS).

198. The method of claim 194, further comprising administering to the subject one or more additional therapeutic agents.

199. The method of claim 198, wherein the one or more additional therapeutic agents are selected from the group consisting of: acetaminophen, one or more NSAIDs, opioid analgesics, and combinations thereof.

200. Use of a compound of formula (I-IV) according to claims 149 to 191 for the manufacture of a medicament for the treatment of a patient suffering from Na _v 1.8 an agent that increases activity or expression of a condition, disease or disorder associated with such disorder in a subject.

201. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R ₁ is-CN, -CF ₃ Optionally substituted 5 or 6 ring membersIncluding aryl or heteroaryl rings, wherein the ring of 5 or 6 ring members optionally includes one or more of N or S in the ring, wherein the substitution on the ring of 5 or 6 ring members is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, CF ₃ 、OCF ₃ A fused heterocyclyl having 5 or 6 members per ring, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl or a partially unsaturated heterocyclyl, each optionally substituted where the valency permits;

R ₂ Is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ halogen, alkyl or alkoxy;

R ₄ halogen, alkyl or H;

x is CH or N; and is also provided with

Z is CH or N, and the Z is CH or N,

wherein X and Z are not both CH;

R ₂ is-CH ₃ 、-CD ₃ or-CT ₃ Wherein D is deuterium and T is tritium;

R ₃ is-CH ₃ 、-CD ₃ or-CT ₃ Wherein D is deuterium and T is tritium.

202. A compound of the formula (IV),

or a pharmaceutically acceptable salt thereof,

wherein:

y is N or CR ₁₃ ；

H. halo, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR', -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH (CH) ₃ ) -cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH (-CH) ₃ ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH ₂ Hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR ' R "-NHSOR ', -NHC (=o) -alkyl-NH (c=o) NR ' R", SO ₂ R', trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sulfonylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, each of which may have one or more substituents, wherein said 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

R ₁₂ 、R ₁₃ and R is ₁₄ Individually selected from: H. CF (compact flash) ₃ Halo, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH (CH) ₃ ) -cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH (-CH) ₃ ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH ₂ Hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR 'R' -NHSO ₂ R1, -NHC (=o) -alkyl-NH (c=o) NR' R ", spirocyclic, morpholino, pyrrolidinyl, piperidinyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the ring of 5 or 6 ring members optionally comprises one or more N or S in the ring, wherein the substitution on the ring of 5 or 6 ring members is selected from the group consisting of: halogen, alkyl Alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, -C (=o) -NH-alkyl, -C (=o) NH ₂ Cyano, CF ₃ 、CHF ₂ 、OCH ₃ 、OCF ₃ A fused heterocyclyl having 5 or 6 members per ring, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl or a partially unsaturated heterocyclyl, each optionally substituted where the valency permits;

the substituents R 'and R' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted, unsubstituted heteroaryl, or CD ₃ 。

203. The compound of claim 202, wherein a is CH ₂ CF ₃ 。

204. The compound of claim 202, wherein a is

205. A compound of the formula (V),

a and B are as described in formula (IV)

R ₂ As described in formula (II)

R ₁₃ And R is ₁₄ As described in formula (IV)

X is CH or N;

y is NR ₈ Or O;

z is CH, N or N-O.

206. A compound of formula (I):

wherein:

R ₁ is-CN, -CF ₃ An optionally substituted ring of 5 or 6 ring members, including aryl or heteroaryl rings, wherein the ring of 5 or 6 ring members optionally includes one or more N or S in the ring, wherein the substitution on the ring of 5 or 6 ring members is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfonimido, alkylsulfonamide, cyano, CF ₃ 、OCF ₃ A fused heterocyclyl having 5 or 6 members per ring, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl or a partially unsaturated heterocyclyl, each optionally substituted where the valency permits;

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ halogen, alkyl or alkoxy;

R ₄ halogen, alkyl or H;

x is CH or N; and is also provided with

Z is CH or N, and the Z is CH or N,

provided that X and Z cannot both be CH,

or a pharmaceutically acceptable salt thereof.

207. The compound of claim 206, wherein R ₂ Selected from the group consisting of: -CH ₃ 、-CD ₃ or-CT ₃ And wherein D is deuterium and T is tritium.

208. The compound of claim 206, wherein R ₃ Selected from the group consisting of: -CH ₃ 、-CD ₃ or-CT ₃ And wherein D is deuterium and T is tritium.

209. The compound of claim 206, wherein R ₅ Optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy or halogen.

210. A compound selected from the compounds described in examples 7-101.

211. A compound selected from the group consisting of the compounds described in examples 103-105.

212. A compound selected from the compounds set forth in examples 110-114.

213. A compound selected from the compounds described in example 119.

214. A compound selected from the compounds described in example 121.