JPWO2019140188A5 - - Google Patents

Description

This application claims the priority benefit of US Provisional Patent Application No. 62 / 616,253 filed on January 11, 2018, the disclosure of which is set forth herein in its entirety. As incorporated herein by reference.

The present disclosure relates to novel dihydroceramide desaturase (Des) inhibitor compounds and compositions, as well as their application as pharmaceuticals for the treatment of diseases. Methods of inhibiting dihydroceramide desaturase 1 (Des1) and / or Des2 activity in human or animal subjects also vary from metabolic, cardiovascular, fibrotic, kidney, autoimmune / chronic inflammatory diseases, and cystic fibrosis. It is provided for the treatment of cancer, lipid storage disorders, neurodegenerative disorders, and ischemic / reperfusion injuries.

Federal-sponsored research or development statement The invention was made with government support under License No. 2 R44 DK116450-02 awarded by the National Institutes of Health. The government has certain rights to the invention.

The dihydroceramide desaturase catalyzes the formation of ceramide by introducing a 4,5-trans double bond into the sphingoid backbone of the dihydroceramide. Studies using cultured cells and isolated muscles reveal that endogenous ceramides and glucosylceramides may antagonize insulin-stimulated glucose uptake and anabolism and thus mimic the effects of extrinsic sphingolipid analogs. I made it. In addition, studies in the rodent model of obesity revealed that the genetic or pharmacological inhibition of ceramide or glucosylceramide biosynthesis is insulin sensitization. Therefore, ceramide overproduction is currently recognized as an important nutrient metabolite that accumulates in obesity, alters cellular metabolism, promotes apoptosis, and thus causes many characteristic events associated with metabolic disorders.

There are at least two isoforms of the human dihydroceramide desaturase protein, Des1 and Des2. Des1 was first identified and expressed in a broader sense, and therefore most of the studies published so far relate to this isoform. Published data can prove that inhibitors of ceramide synthesis, ie, inhibitors of hydroceramide desaturase (eg, Des1), are effective therapeutic agents for the treatment of insulin resistance and metabolic disorders. It suggests. In addition, published data show that inhibitors of dihydroceramide desaturase (eg, Des1) can be used in a variety of cancers, cystic fibrosis, fibrotic disorders, cardiovascular disorders, autoimmune / chronic inflammatory disorders, and ischemia. It suggests that it can also be proven to be effective as a therapeutic agent for treating reperfusion injury.

Certain novel compounds and pharmaceutical compositions found to inhibit dihydroceramide desaturase have been discovered along with methods of synthesizing the compounds and using them, including methods of treating metabolic disorders in patients by administration of the compounds. Has been done.
Detailed description

式中、
Ｌが、－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－、－ＮＲ_３Ｓ（＝Ｏ）_２－、－ＮＲ_３Ｃ（＝Ｏ）－、および－ＯＣ（＝Ｏ）－から選択され、
Ｗが、－ＮＨ－および－Ｏ－から選択され、
Ｒ^１が、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリールから選択され、それらのいずれもが１、２、もしくは３個のＲ^５基で任意に置換されていてもよく、
Ｒ^２が、アリールおよびヘテロアリールから選択され、１、２、もしくは３個のＲ^４基で任意に置換されていてもよく、
Ｒ^３がＨであるか、またはアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリールから選択され、それらのいずれもが１、２、もしくは３個のＲ^５基で任意に置換されていてもよく、あるいは、Ｒ^３が、Ｒ^１および介在するＮと結合してヘテロシクロアルキルを形成し、それは、１、２、または３個のＲ^５基で任意に置換されていてもよく、
Ｒ^４の少なくとも１つがヒドロキシであり、他は１つ以上の他の任意の置換基であってよく、
各Ｒ^５が独立して、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、（アリール）アルキル、（ヘテロアリール）アルキル、（アリール）アリール、（ヘテロアリール）アリール、（アリール）ヘテロアリール、および（ヘテロアリール）ヘテロアリールから選択され、１、２、または３個のＲ^６基で任意に置換されていてもよく、
各Ｒ^６が独立して、アルコキシ、アルキル、アミノ、カルボキシ、シアノ、ハロ、ハロアルコキシ、ハロアルキル、およびヒドロキシから選択される。 The first embodiment provided herein is a compound having the structure of the following formula (I) or a salt thereof.

During the ceremony
L is from -C (= O)-, -S (= O) _2- , -NR ₃ S (= O) _2- , -NR ₃ C (= O)-, and -OC (= O)- Selected
W is selected from -NH- and -O-
R ¹ may be selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be optionally substituted with 1, 2, or ³ R5 groups.
^R2 may be selected from aryl and heteroaryl and optionally substituted with 1, 2, or 3 ^R4 groups.
R ³ is H or is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or ³ R5 groups. Alternatively, R ³ may combine with R ¹ and the intervening N to form a heterocycloalkyl, which may be optionally substituted with 1, 2, or 3 R ⁵ groups.
At least one of ^R4 may be hydroxy and the other may be one or more other arbitrary substituents.
Each R ⁵ is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, And (heteroaryl) Heteroaryl, optionally substituted with 1, ² , or 3 R6 groups.
Each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.

The specific compounds disclosed herein have useful Des1 inhibitory activity and can be used to treat or prevent a disease or condition in which Des1 acts. Accordingly, in a broad embodiment, a particular embodiment, together with a pharmaceutically acceptable carrier, manufactures and uses a pharmaceutical composition comprising one or more compounds disclosed herein, and the compounds and compositions. It also provides a method. Certain embodiments provide methods for inhibiting Des1. Another embodiment provides a method of treating a Des1-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the invention. .. Also provided are the use of certain compounds disclosed herein for use in the manufacture of a pharmaceutical for the treatment of a disease or condition that is ameliorated by inhibition of Des1.

In certain embodiments, L is −C (= O) −.

In a particular embodiment, L is selected from −S (= O) _2- , −NR ₃ S (= O) _2- .

In a particular embodiment, L is −S (= O) _2- .

In a particular embodiment, L is −NR ₃ S (= O) _2- .

In certain embodiments, L is selected from -NR ₃ C (= O)-and -OC (= O)-.

In certain embodiments, L is −NR ₃ C (= O) −.

In certain embodiments, L is —OC (= O) −.

In certain embodiments, W is -NH-.

In certain embodiments, W is —O—.

In certain embodiments, R ² is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and is optionally substituted with one or two ^R4 groups.

In certain embodiments, R ² is selected from phenyl, pyridinyl, pyridadinyl, and pyrazinyl and replaced with one or two ^R4 groups.

In certain embodiments, R ² is selected from phenyl and pyridin-2-yl and replaced with one or two R ⁴ groups.

In certain embodiments, R ² is selected from phenyl and pyridine-2-yl and optionally substituted with one or two R ⁴ groups.

In certain embodiments, R ³ combines with R ¹ and the intervening N to form a heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups.

In certain embodiments, R ³ combines with R ¹ and the intervening N to form a 6-membered heterocycloalkyl, which is optionally substituted with one or two R ⁵ groups.

In certain embodiments, R ³ binds to R ¹ and the intervening N to form a piperidine or piperazine ring substituted with R ⁵ groups.

In certain embodiments, R ³ combines with R ¹ and the intervening N to form a 7-membered heterocycloalkyl, which is optionally substituted with one or two R ⁵ groups.

In certain embodiments, R ³ binds to R ¹ and the intervening N to form an azepane or diazepane ring substituted with R ⁵ groups.

^In certain embodiments, R5 is selected from alkyl and heteroalkyl and optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is selected from phenyl and pyridinyl and optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is phenyl optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is a pyridinyl optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is selected from (aryl) alkyl and (heteroaryl) alkyl, any of which is optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is selected from (aryl) methyl and (heteroaryl) methyl, any of which is optionally substituted with one or ^two R6 groups.

^In certain embodiments, R5 is (phenyl) methyl and is optionally substituted with one or ^two R6 groups.

In certain embodiments, R5 is ² -fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4- (trifluoromethyl) phenyl, 4- (trifluoromethyl) pyridin-2-yl, 5 -(Trifluoromethyl) Pyridine-2-yl, 5-fluoropyridine-2-yl, and 3,5-difluoropyridine-2-yl are selected.

^In certain embodiments, R5 is selected from 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, and 4- (trifluoromethyl) phenyl.

In certain embodiments, R5 is 4- (trifluoromethyl) pyridin-2-yl, ^5- (trifluoromethyl) pyridin-2-yl, 5-fluoropyridine-2-yl, and 3,5-. It is selected from difluoropyridin-2-yl.

In certain embodiments, R5 is ⁴ -fluorophenyl, 4- (trifluoromethyl) phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 5-fluoropyridine-2-yl, and 5- ( It is selected from trifluoro) pyridine-2-yl.

^In certain embodiments, each R6 is independently selected from halo, haloalkyl, and cyano.

^In certain embodiments, each R6 is independently selected from halo and haloalkyl.

^In certain embodiments, each R6 is independently selected from fluoro, chloro, and trifluoromethyl.

^In certain embodiments, each R6 is independently selected from fluoro and chloro.

^In certain embodiments, each R6 is independently selected from fluoro and trifluoromethyl.

The present disclosure provides a further embodiment:

Embodiment 2: In the formula,
Each R ⁴ is independently selected from alkyl, alkoxy, cyano, halo, and hydroxy.
The compound according to embodiment 1, wherein at least one ^R4 is hydroxy.

Embodiment 3: In the formula,
Each R ⁴ is independently selected from cyano, halo, and hydroxy,
The compound according to embodiment 2, wherein at least one ^R4 is hydroxy.

Embodiment 4: The compound according to embodiment 3, wherein each R ⁴ is hydroxy in the formula.

Embodiment 5: In the formula, any of embodiments 1 to 4, wherein R ² is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and optionally substituted with 1, 2, or 3 ^R4 groups. The compound according to one.

Embodiment 6: In the formula, R ² is selected from phenyl, pyridine-2-yl, pyridazine-3-yl, pyrimidine-2-yl, and pyrazine-2-yl, and 1, 2, or 3 Rs. The compound according to embodiment 5, which is optionally substituted with ⁴ units.

Embodiment 7: In the formula, R ² is selected from phenyl, pyridine-2-yl, pyridazine-3-yl, and pyrimidine-2-yl and optionally substituted with 1, 2, or 3 R ⁴ groups. The compound according to the fifth embodiment.

Embodiment 8: The compound according to embodiment 7, wherein R ² is selected from phenyl and pyridin-2-yl in the formula and optionally substituted with 1, 2, or 3 R ⁴ groups.

Embodiment 9: The compound according to embodiment 8, wherein R ² is pyridine-2-yl in the formula and is substituted with 1, 2, or 3 R ⁴ groups.

Embodiment 10: In the formula,
^R2 is replaced with 1, 2, or 3 ^R4 groups
The compound according to any one of embodiments 1 to 9, wherein at least one ^R4 is hydroxy.

Embodiment 11: In the formula,
R ² is replaced with 1 or 2 R ⁴ groups
The compound according to embodiment 10, wherein at least one ^R4 is hydroxy.

Embodiment 12: The compound according to embodiment 11, wherein R ² is substituted with one hydroxy group in the formula.

13: The compound according to any one of embodiments 10-12, wherein R ² is substituted with ⁴ R groups at the para position from the binding point of W in the formula.

Embodiment 14: The compound according to embodiment 13, wherein R ² is substituted with hydroxy at the para position from the binding point of W in the formula.

Embodiment 15: The compound according to embodiment 1, wherein ^R2 is 4-hydroxyphenyl in the formula.

Embodiment 16: The compound according to embodiment 1, wherein ^R2 is 5-hydroxypyridin-2-yl in the formula.

17: The compound according to embodiment 1, wherein ^R2 is 5-hydroxypyrimidine-2-yl in the formula.

18: The compound according to embodiment 1, wherein ^R2 is 5-hydroxypyrazine-2-yl in the formula.

Embodiment 19: The compound according to embodiment 1, wherein ^R2 is 6-hydroxypyridazine-3-yl in the formula.

20: The compound according to any one of embodiments 1 to 19, wherein W is -NH- in the formula.

21: The compound according to any one of embodiments 1 to 19, wherein W is —O— in the formula.

22: In the formula, L is selected from —C (= O) −, —S (= O) _2- , and —OC (= O) −, any one of embodiments 20 and 21. The compound described in.

23: The compound according to embodiment 22, wherein L is −C (= O) − in the formula.

24: The compound according to embodiment 22, wherein L is —S (= O) ₂ -in the formula.

25: The compound according to embodiment 22, wherein L is —OC (= O) − in the formula.

26: The compound according to any one of embodiments 20 and 21, wherein L is selected from −NR ³ S (= O) ₂ − and −NR ³ C (= O) − in the formula.

27: The compound according to embodiment 26, wherein L is −NR ³ S (= O) ₂ -in the formula.

28: The compound according to embodiment 26, wherein L is −NR ³ C (= O) − in the formula.

29: The compound according to any one of embodiments 1 to 19, wherein LW is −NR ³ C (= O) NH— in the formula.

30: The compound according to any one of embodiments 1 to 19, wherein LW is −NR ³ C (= O) O— in the formula.

31: The compound according to any one of embodiments 1 to 19, wherein LW is −NR ³ S (= O) ₂ NH— in the formula.

Embodiment 32: The compound according to any one of embodiments 1 to 19, wherein LW is —OC (= O) NH— in the formula.

33: The compound according to any one of embodiments 1 to 19, wherein LW is —S (= O) ₂ NH— in the formula.

式中、
Ｗが、－ＮＨ－および－Ｏ－から選択され、
ＸおよびＹが独立して、ＣＨおよびＮから選択され、
Ｒ^５が、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、（アリール）アルキル、（ヘテロアリール）アルキル、（アリール）アリール、（ヘテロアリール）アリール、（アリール）ヘテロアリール、および（ヘテロアリール）ヘテロアリールから選択され、１、２、または３個のＲ^６基で任意に置換され、
各Ｒ^６が独立して、アルコキシ、アルキル、アミノ、カルボキシ、シアノ、ハロ、ハロアルコキシ、ハロアルキル、およびヒドロキシから選択され、
ｎが、１および２から選択される、実施形態３４の実施形態１の化合物またはその塩が提供される。 Further, in the present specification, the structural formula II is provided.

During the ceremony
W is selected from -NH- and -O-
X and Y are independently selected from CH and N,
R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ⁽ aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, and (heteroaryl). ) Selected from heteroaryl, optionally substituted with 1, 2, or ³ R6 groups,
Each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.
The compound of embodiment 1 of embodiment 34 or a salt thereof, wherein n is selected from 1 and 2, is provided.

In certain embodiments of the compounds of formula II, X is N.

In certain embodiments of the compounds of formula II, X is CH.

In a particular embodiment of the compound of formula II, n is 1.

In a particular embodiment of the compound of formula II, n is 2.

式中、
ＸおよびＹが独立して、ＣＨおよびＮから選択され、
Ｒ^５が、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、（アリール）アルキル、（ヘテロアリール）アルキル、（アリール）アリール、（ヘテロアリール）アリール、（アリール）ヘテロアリール、および（ヘテロアリール）ヘテロアリールから選択され、１、２、または３個のＲ^６基で任意に置換され、
各Ｒ^６が独立して、アルコキシ、アルキル、アミノ、カルボキシ、シアノ、ハロ、ハロアルコキシ、ハロアルキル、およびヒドロキシから選択され、
ｎが、１および２から選択される、実施形態３５の実施形態１の化合物またはその塩が提供される。 Further, in the present specification, it has structural formula III and has.

During the ceremony
X and Y are independently selected from CH and N,
R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ⁽ aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, and (heteroaryl). ) Selected from heteroaryl, optionally substituted with 1, 2, or ³ R6 groups,
Each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.
The compound of embodiment 1 of embodiment 35 or a salt thereof, wherein n is selected from 1 and 2, is provided.

36: The compound according to any one of embodiments 34 and 35, wherein N is 1 in the formula.

Embodiment 37: The compound according to any one of embodiments 34 and 35, wherein N is 2 in the formula.

38: The compound according to any one of embodiments 34 to 37, wherein Y is CH in the formula.

39: The compound according to any one of embodiments 34 to 37, wherein Y is N in the formula.

Ｘが、ＣＨおよびＮから選択され、
Ｒ^１が、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリールから選択され、それらのいずれもが１、２、または３個のＲ^５基で任意に置換されるか、または
Ｒ^３がＨであるか、またはアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリールから選択され、それらのいずれもが１、２、もしくは３個のＲ^５基で任意に置換されるか、あるいはＲ^３が、Ｒ^１および介在するＮと結合してヘテロシクロアルキルを形成し、これは、１、２、または３個のＲ^５基で任意に置換され、
各Ｒ^５が独立して、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、（アリール）アルキル、および（ヘテロアリール）アルキルから選択され、１、２、または３個のＲ^６基で任意に置換され、
各Ｒ^６が独立して、アルコキシ、アルキル、アミノ、カルボキシ、シアノ、ハロ、ハロアルコキシ、ハロアルキル、およびヒドロキシから選択される、実施形態４０の実施形態１の化合物が提供される。 Further, in the present specification, it has the structural formula IV and has.

X is selected from CH and N
R ¹ is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or 3 R ⁵ groups, or R ³ is H or selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or ³ R5 groups, or R. ³ combines with R ¹ and the intervening N to form a heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups.
Each R ⁵ is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl) alkyl, and (heteroaryl) alkyl and is optional with 1, 2, or ³ R6 groups. Replaced by
The compound of Embodiment 1 of Embodiment 40 is provided, wherein each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.

Ｘが、ＣＨおよびＮから選択され、
Ｒ^３がＨであるか、またはアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、およびヘテロアリールから選択され、それらのいずれもが１、２、もしくは３個のＲ^５基で任意に置換されるか、あるいはＲ^３が、Ｒ^１および介在するＮと結合してヘテロシクロアルキルを形成し、これは、１、２、または３個のＲ^５基で任意に置換され、
各Ｒ^５が独立して、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、（アリール）アルキル、および（ヘテロアリール）アルキルから選択され、１、２、または３個のＲ^６基で任意に置換され、
各Ｒ^６が独立して、アルコキシ、アルキル、アミノ、カルボキシ、シアノ、ハロ、ハロアルコキシ、ハロアルキル、およびヒドロキシから選択される、実施形態４１の実施形態１の化合物が提供される。 Further, in the present specification, the structural formula V is provided.

X is selected from CH and N
Whether R ³ is H or is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or ³ R5 groups. , Or R ³ binds to R ¹ and the intervening N to form a heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups.
Each R ⁵ is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl) alkyl, and (heteroaryl) alkyl and is optional with 1, 2, or ³ R6 groups. Replaced by
The compound of Embodiment 1 of Embodiment 41 is provided, wherein each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.

42: The compound according to any one of embodiments 34 to 41, wherein X is CH.

Embodiment 43: The compound according to any one of embodiments 34 to 41, wherein X is N.

Embodiment 44: The compound according to any one of embodiments 26 to 31 and 41, wherein R ³ is H in the formula.

Embodiment 45: In the formula, R ³ is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with 1, 2, or 3 R ⁵ groups. The compound according to any one of embodiments 26 to 31 and 41.

Embodiment 46: In the formula, R ³ combines with R ¹ and an intervening N to form a heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups. The compound according to any one of forms 26 to 31 and 41.

Embodiment 47: In the formula, R ³ combines with R ¹ and the intervening N to form a 6-membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups. , The compound according to embodiment 46.

Embodiment 48: In the formula, R ³ combines with R ¹ and an intervening N to form a piperidine or piperazine ring, which is optionally substituted with 1, 2, or 3 R ⁵ groups. The compound according to embodiment 47.

Embodiment 49: In the formula, R ³ combines with R ¹ and the intervening N to form a 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups. , The compound according to embodiment 46.

Embodiment 50: In the formula, R ³ combines with R ¹ and an intervening N to form an azepane or diazepane ring, which is optionally substituted with 1, 2, or 3 R ⁵ groups. The compound according to embodiment 49.

51: Any of embodiments 46-50, wherein in the formula, the heterocycloalkyl formed by the bonds of R ³ , R ¹ , and the intervening N are optionally substituted with one or two R ⁵ groups. The compound according to one.

52: The compound according to embodiment 51, wherein in the formula, the heterocycloalkyl formed by the binding of R ³ , R ¹ and the intervening N is replaced with one or two R ⁵ groups.

Embodiment 53: The compound according to embodiment 51, wherein the heterocycloalkyl formed by the binding of R ³ , R ¹ and the intervening N in the formula is optionally substituted with 1R ⁵ groups.

54: The compound according to embodiment 53, wherein the heterocycloalkyl formed by the bonds of R ³ , R ¹ , and intervening N is replaced by one R ⁵ group.

Embodiment 55: The compound according to embodiment 53, wherein the heterocycloalkyl formed by the binding of R ³ , R ¹ and the intervening N in the formula is unsubstituted.

Embodiment 56: In the formula, R ¹ is selected from C _1-16 alkyl, C _3-7 cycloalkyl, 3-7 member monocyclic heterocycloalkyl, C _6-10 aryl, and 5-10 member heteroaryl. The compound according to any one of embodiments 1 to 45, wherein any of them is optionally substituted with 1, 2, or ³ R5 groups.

Embodiment 57: In the formula, R ¹ is selected from cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, pyrrolidinyl, piperidinyl, and azepanyl, any of which is 1, 2, or 3. The compound according to embodiment 56, which is optionally substituted with ⁵ R groups.

Embodiment 58: In the formula, R ¹ is selected from cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, any of which is optionally substituted with 1, 2, or 3 R ⁵ groups. The compound according to embodiment 57.

Embodiment 59: In the formula, R ¹ is selected from phenyl, naphthalenyl, quinolinyl, isoquinolinyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrimidinyl, and pyrazinyl, all of which are 1, 2, or 3 R ^5s . The compound according to embodiment 56, which is optionally substituted.

Embodiment 60: The compound of embodiment 59, wherein ^R1 is selected from phenyl and pyridine in the formula, any of which is optionally substituted with 1, 2, or ³ R5 groups. ..

Embodiment 61: The compound according to embodiment 56, wherein R ¹ is C _1-12 alkyl in the formula and is optionally substituted with 1, 2, or 3 R ⁵ groups.

Embodiment 62: The compound according to embodiment 61, wherein R ¹ is C _1-10 alkyl in the formula and is optionally substituted with 1, 2, or 3 R ⁵ groups.

Embodiment 63: The compound of embodiment 62, wherein R ¹ is C _1-8 alkyl in the formula and is optionally substituted with 1, 2, or 3 R ⁵ groups.

Embodiment 64: The compound according to embodiment 63, wherein R ¹ is C _4-8 alkyl in the formula and is optionally substituted with 1, 2, or 3 R ⁵ groups.

Embodiment 65: The compound according to embodiment 64, wherein R ¹ is C _6-8 alkyl in the formula and is optionally substituted with 1, 2, or 3 R ⁵ groups.

Embodiment 66: The compound according to any one of embodiments 1-45 and ^56-65 , wherein R1 is optionally substituted with ^one or two R5 groups in the formula.

Embodiment 67: The compound of embodiment 66, wherein R1 is substituted with ^one or two ^R5 groups in the formula.

Embodiment 68: The compound according to embodiment 66, wherein R ¹ is optionally substituted with ⁵ units of 1R in the formula.

Embodiment 69: The compound according to embodiment 68, wherein R ¹ is substituted with one R ⁵ group in the formula.

Embodiment 70: The compound according to embodiment 66, wherein ^R1 is unsubstituted in the formula.

Embodiment 71: In the formula,
R ¹ is (CH ₂ ) _m CH ₃ and
The compound according to embodiment 56, wherein m is an integer between 3 and 15.

Embodiment 72: The compound according to embodiment 71, wherein m is less than 14 in the formula.

Embodiment 73: The compound according to embodiment 72, wherein m is less than 12 in the formula.

Embodiment 74: The compound according to embodiment 73, wherein m is less than 10 in the formula.

Embodiment 75: The compound according to embodiment 74, wherein m is less than 8 in the formula.

Embodiment 76: The compound according to embodiment 75, wherein m is less than 6 in the formula.

Embodiment 77: The compound according to any one of embodiments 71 to 76, wherein m is greater than 4 in the formula.

Embodiment 78: The compound according to any one of embodiments 71 to 75, wherein m is greater than 6 in the formula.

Embodiment 79: The compound according to any one of embodiments 71 to 74, wherein m is greater than 8 in the formula.

80: The compound according to any one of embodiments 71 to 73, wherein m is greater than 10 in the formula.

から選択される、実施形態５６に記載の化合物。 Embodiment 81: In the formula, R ¹ is

56. The compound according to embodiment 56, which is selected from.

から選択される、実施形態５６に記載の化合物。 Embodiment 82: In the formula, R ¹ is

56. The compound according to embodiment 56, which is selected from.

Embodiment 83: The compound according to any one of embodiments 81 and 82, wherein L is −C (= O) in the formula.

Embodiment 84: The compound according to embodiment 83, wherein W is —NH— in the formula.

Embodiment 85: In the formula, R ⁵ is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl) methyl, and (heteroaryl) methyl and 1, 2, or 3 R ^6s . The compound according to any one of embodiments 1-54, 56-69, and 81-84, which is optionally substituted with a group.

Embodiment 86: ^In embodiment 85, where R5 is selected from phenyl, naphthyl, monocyclic heteroaryl, and bicyclic heteroaryl and optionally substituted with one or ^two R6 groups. The compound described.

Embodiment 87: ^In the formula, R5 is selected from quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, and imidazolypyridinyl and optionally substituted with one or ^two R6 groups, according to embodiment 86. The compound described.

Embodiment 88: The compound of embodiment 87, wherein R5 is ^indazolyl in the formula and is optionally substituted with one or ^two R6 groups.

Embodiment 89: The compound of embodiment 88, wherein R5 is selected from indazole- ⁴ -yl and indazole- ⁶ -yl in the formula and optionally substituted with one or two R6 groups.

^Example 90: The compound according to embodiment 86, wherein R5 is selected from pyrrolyl, imidazolyl, and pyrazolyl and optionally substituted with one or ^two R6 groups in the formula.

Embodiment 91: The compound according to embodiment 86, wherein ^R5 is selected from indolyl and indazolyl in the formula and optionally substituted with one or ^two R6 groups.

Embodiment 92: The compound according to embodiment 86, wherein R5 is selected from phenyl, pyridinyl, ^pyridadinyl , pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups in the formula.

Embodiment 93: The compound according to embodiment 86, wherein ^R5 is selected from phenyl, pyridinyl, and pyrimidinyl in the formula and optionally substituted with one or ^two R6 groups.

Embodiment 94: The embodiment 86, wherein R5 is selected from phenyl, pyridine- ² -yl, and pyrimidine-2-yl and optionally substituted with one or ^two R6 groups in the formula. Compound.

Embodiment 95: The compound according to embodiment 85, wherein R5 is selected from ⁽ aryl) alkyl, (heteroaryl) alkyl in the formula and optionally substituted with one or ^two R6 groups.

Embodiment 96: The compound according to embodiment 95, wherein R5 is selected from ⁽ aryl) methyl, (heteroaryl) methyl in the formula and optionally substituted with one or ^two R6 groups.

Embodiment 97: The compound according to embodiment 96, wherein R5 is ⁽ phenyl) methyl in the formula and is optionally substituted with one or ^two R6 groups.

Embodiment 98: One of embodiments 1-54, 56-69, 81-84, and 85-97, wherein each R ⁵ is optionally substituted with one or two R ⁶ groups. The compound described in.

Embodiment 99: The compound according to embodiment 98, wherein each R ⁵ is substituted with one or two R ⁶ groups in the formula.

Embodiment 100: The compound according to embodiment 98, wherein each R ⁵ is optionally substituted with one R ⁶ group in the formula.

Embodiment 101: The compound according to embodiment 100, wherein each R ⁵ is substituted with one R ⁶ group in the formula.

Embodiment 102: The compound according to embodiment 100, wherein each R ⁵ is unsubstituted in the formula.

Embodiment 103: In the formula, each R ⁶ is independently selected from alkoxy, alkyl, amino, cyano, halo, haloalkoxy, haloalkyl, and hydroxy, embodiments 1-54, 56-69, 81-84. , And the compound according to any one of 85 to 101.

Embodiment 104: The compound of embodiment 103, wherein each R ⁶ is independently selected from cyano, halo, hydroxy, and haloalkyl in the formula.

Embodiment 105: The compound of embodiment 104, wherein each R ⁶ is independently selected from halo and haloalkyl in the formula.

Embodiment ¹⁰⁶ : The compound of embodiment 105, wherein each R6 is independently selected from fluoro, chloro, and trifluoromethyl in the formula.

Embodiment 107: The compound of embodiment 106, wherein each R ⁶ is independently selected from halo and trifluoromethyl in the formula.

Embodiment 108: The compound according to embodiment 103, wherein each R ⁶ is independently selected from fluoro, chloro, methoxy, methyl, cyano, trifluoromethyl, and trifluoromethoxy in the formula.

The following embodiments are also provided:
Embodiment C-2: In the formula, L is -S (= O) _2- , -NR ₃ S (= O) _2- , -NR ₃ C (= O)-, and -OC (= O)-. The compound of Embodiment 1 selected from.

Embodiment C-3: A compound of embodiment C-2, wherein each R ⁴ is independently selected from cyano, halo, and hydroxy in the formula.

Embodiment C-4: A compound of embodiment C-3, wherein R ² is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and substituted with one or two ^R4 groups in the formula.

Embodiment C-5: In the formula, ^R2 is replaced with ^R4 group at the para position from the binding point of W, the compound of embodiment C-4.

であり、
Ｘが、ＣＨおよびＮから選択される、実施形態Ｃ－５の化合物。 Embodiment C-6: In the formula,
R ² is

And
The compound of embodiment C-5, where X is selected from CH and N.

Embodiment C-7: The compound of embodiment C-6, wherein L is −NR ₃ C (= O) − in the formula.

Embodiment C-8: The compound of embodiment C-7, wherein L is —OC (= O) − in the formula.

Embodiment C-10: The compound of embodiment 34, wherein X is N in the formula.

Embodiment C-11: A compound of Embodiment C- ¹⁰ in which R5 is selected from aryl and heteroaryl and optionally substituted with one or ^two R6 groups.

Embodiment C-12: The compound of embodiment C- ¹¹ , wherein each R6 is independently selected from alkyl, halo, haloalkyl, and hydroxy in the formula.

Embodiment C-13: In the formula, R ⁵ is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups, the compound of embodiment C-12.

Embodiment C-14: A compound of embodiment C- ¹³ , wherein each R6 is independently selected from halo and trifluoromethyl in the formula.

Embodiment C-15: The compound of embodiment C-14, wherein n is 1 in the formula.

Embodiment C-16: The compound of embodiment C-15, wherein W is NH in the formula.

Embodiment C-17: The compound of embodiment C-16, wherein Y is N in the formula.

Embodiment C-18: A compound of embodiment C- ¹⁷ in which R5 is selected from phenyl and pyridin-2-yl and optionally substituted with one or ^two R6 groups.

Embodiment C-19: A compound of embodiment C- ¹⁸ , wherein each R6 is independently selected from fluoro and trifluoromethyl in the formula.

Embodiment C-20: ^In the formula, R5 is 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4- (trifluoromethyl) phenyl, 4- (trifluoromethyl) pyridine-2- The compound of embodiment C-19, selected from yl, 5- (trifluoromethyl) pyridine-2-yl, 5-fluoropyridine-2-yl, and 3,5-difluoropyridine-2-yl.

Embodiment C-21: The compound of embodiment C-20, wherein R5 is 2,4 ^- difluorophenyl in the formula.

Embodiment C-23: The compound of embodiment 35, wherein X is N in the formula.

Embodiment C-24: The compound of embodiment C-23, wherein Y is N in the formula.

Embodiment C-25: A compound of embodiment C ^- 24, wherein each R6 is independently selected from halo and trifluoromethyl in the formula.

Embodiment C-26: ^In the formula, R5 is a compound of embodiment C-25 selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups.

Embodiment C-27: A compound of embodiment C ^- 26 in which R5 is selected from phenyl and pyridin-2-yl and optionally substituted with one or ^two R6 groups.

Embodiment C-28: A compound of embodiment C ^- 27, wherein each R6 is independently selected from fluoro and chloro in the formula.

Embodiment C-29: In the formula, R5 is ⁴ -fluorophenyl, 4-chlorophenyl, 4- (trifluoromethyl) phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 5-fluoropyridine-2. -The compound of embodiment C-28 selected from 5-yl and 5- (trifluoro) pyridine-2-yl.

から選択される、実施形態１の化合物。 Embodiment C-30:

The compound of Embodiment 1 selected from.

Also provided are embodiments in which any of the above embodiments can be combined with any one or more of these embodiments, but the combinations are not mutually exclusive.

As used herein, two embodiments are "mutually exclusive" when one is defined as different from the other. For example, an embodiment in which two groups are bonded to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH ₂ is mutually exclusive with an embodiment in which the same group is NH.

Compounds selected from the examples disclosed herein are also provided.

The invention also relates to a method of inhibiting at least one Des1 function, comprising contacting Des1 with a compound described herein. Cell phenotype, cell proliferation, activity of Des1, changes in biochemical output produced by active Des1, expression of Des1, or binding of Des1 to its native binding partner can be monitored. Such methods can be disease treatment modalities, biological assays, cell assays, biochemical assays and the like.

Also provided herein are methods of treating Des1-mediated diseases, comprising administering a therapeutically effective amount of a compound or salt thereof disclosed herein to a patient in need thereof.

Also provided herein are the compounds disclosed herein for use as agents.

Also provided herein are the compounds disclosed herein for use as agents to treat Des1-mediated diseases.

The use of the compounds disclosed herein as agents is also provided.

Also provided are the use of the compounds disclosed herein as agents to treat Des1-mediated diseases.

Also provided are the compounds disclosed herein for use in the manufacture of agents for the treatment of Des1-mediated diseases.

Also provided are the use of the compounds disclosed herein to treat Des1-mediated diseases.

Also provided herein are methods of inhibiting Des1, including contacting Des1 with a compound or salt thereof disclosed herein.

In certain embodiments, Des1-mediated disorders include metabolic syndrome, diabetes, dyslipidemia, hypertriglidemia, hypercholesterolemia, fatty liver disease, alcoholic liver disease, nonalcoholic steatohepatitis, obesity, and insulin. It is a metabolic disorder selected from resistance.

In some embodiments, the Des1-mediated disease is a lipid accumulation disorder selected from Faber's disease, Niemann-Pick's disease, Fabry's disease, Clave's disease, Gaucher's disease, Tay-Sax's disease, and allogeneic leukodystrophy.

In certain embodiments, the Des1-mediated disease is an autoimmune disease.

In certain embodiments, the Des1-mediated disease is a chronic inflammatory disease.

In certain embodiments, the Des1-mediated disease is a cardiovascular disease.

In certain embodiments, the Des1-mediated disease is fibrosis or a related disease.

In certain embodiments, Des1-mediated fibrosis includes pulmonary fibrosis, cystic fibrosis, liver fibrosis, liver cirrhosis, atrial fibrosis, endocardial myocardial fibrosis, articular fibrosis, myeloid fibrosis, glia scars, It is selected from Peylony's disease, progressive massive fibrosis, dust pneumonia, retroperitoneal fibrosis, scleroderma, systemic sclerosis, abdominal adhesions, and adhesive arthritis.

In certain embodiments, Des1-mediated fibrosis is cystic fibrosis.

In certain embodiments, the Des1-mediated disease is cancer.

In certain embodiments, the Des1-mediated cancers are leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colon rectal cancer), rectal cancer, bladder cancer, lung cancer (non-). Small cell lung cancer, lung adenocarcinoma, lung squamous epithelial cancer), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, bile sac cancer, bile duct cancer, esophageal cancer , Renal cell cancer, thyroid cancer, head and neck squamous epithelial cancer (head and neck cancer), testis cancer, endocrine cancer, adrenal cancer, pituitary cancer, skin cancer, soft part Tissue cancer, vascular cancer, brain cancer, nerve cancer, eye cancer, medullary cancer, mesopharyngeal cancer, hypopharyngeal cancer, cervical cancer, And uterine cancer, glioma, medullary blastoma, stellate cystoma, glioma, meningitis, gastrinoma, neuroblastoma, melanoma, myelodystrophy syndrome, and sarcoma.

Also provided are the use of the compounds disclosed herein to treat ischemic / reperfusion injury.

It also occurs in organ transplants, acute renal injury, cardiopulmonary bypass, pulmonary hypertension, sickle erythema, myocardial infarction, stroke, surgical resection and reconstructive surgery, rejoining of appendages or other body parts, skin transplants, or trauma. Also provided are the use of the compounds disclosed herein for the treatment of ischemic / reperfusion injury.

Also provided are methods of regulating Des1-mediated function in a subject, including administration of therapeutically effective amounts of the compounds disclosed herein.

Also provided are pharmaceutical compositions comprising the compounds disclosed herein with a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated for oral administration.

In certain embodiments, the oral pharmaceutical composition is selected from tablets and capsules.

Abbreviations and Definitions As used herein, the following terms have the indicated meanings.

When introducing the elements of the present disclosure or preferred embodiments thereof (s), the articles "a", "an", "the", and "said" indicate that one or more of the elements are present. Intended to mean. The terms "comprising," "inclating," and "having" are intended to be inclusive and mean that additional elements other than those listed may exist. do.

When the term "and / or" is used in a list of two or more items, any one of the listed items is either itself or one of the listed items. It means that it can be used in combination with the above. For example, the expression "A and / or B" is intended to mean either or both of A and B, ie, A only, B only, or a combination of A and B. The expression "A, B, and / or C" is A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. Is intended to mean.

Not specified if the range of values is disclosed and the notation "n ₁ ... to n ₂ " or "n ₁ ... to n ₂ " is used and n ₁ and n ₂ are numbers. As long as this notation is intended to include the numbers themselves and the range between them. This range can be integer or continuous between and within the closing price. As an example, the range of "2-6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons because carbon is an integer unit. As an example, the range of "1-3 μM (micromol)" intended to include 1 μM, 3 μM, and all between them, can be any number of significant numbers (eg, 1.255 μM, 2.1 μM, etc.). 2.9999 μM, etc.).

As used herein, the term "about" is intended to qualify the numerical value by which it indicates such a value as a variable within the margin of error. If a graph or table of data does not enumerate certain errors, such as the standard deviation for a given mean, the term "about" means that number, taking into account the range that includes the enumerated values and the significant numbers. It should be understood to mean the range included by rounding up or down to.

As used herein, the term "acyl", alone or in combination, can be any alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic carbonyl, or any carbonyl-bonded atom that is carbon. Refers to other parts. The "acetyl" group refers to _three -C (O) CH groups. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to a parent molecule moiety via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

As used herein, the term "alkenyl" refers to straight or branched hydrocarbon radicals that have one or more double bonds and contain 2 to 20 carbon atoms, either alone or in combination. Point. In certain embodiments, the alkenyl will contain 2-6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system bonded to two or more positions such as ethenylene [(-CH = CH-), (-C :: C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include an "alkenylene" group.

As used herein, the term "alkoxy", alone or in combination, refers to an alkyl ether group, as the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

As used herein, the term "alkyl" refers to straight or branched chain alkyl radicals containing 1 to 20 carbon atoms, alone or in combination. In certain embodiments, the alkyl will contain 1-10 carbon atoms. In a further embodiment, the alkyl will contain 1-6 carbon atoms. Alkyl groups can be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, noyl and the like. As used herein, the term "alkylene" is a saturated fat derived from a linear or branched saturated hydrocarbon linked at two or more positions, such as methylene (-CH _2- ), alone or in combination. Refers to a tribe. Unless otherwise specified, the term "alkyl" may include an "alkylene" group.

The term "linear alkyl" refers to an alkyl radical containing 1 to 20 carbon atoms in a straight chain sequence without branches. Examples of linear alkyl radicals are n-octyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _2- ), n-butyl (-CH ₂ CH ₂ CH ₂ CH _2- ), and Includes ethyl (-CH ₂ CH _2- ).

As used herein, the term "alkylamino" refers to an alkyl group attached to a parent molecule moiety via an amino group, alone or in combination. Suitable alkylamino groups can be mono or dialkylated to form groups such as, for example, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-ethylmethylamino and the like.

As used herein, the term "alkylidene" refers to an alkenyl group to which one carbon atom of a carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached, alone or in combination.

As used herein, the term "alkylthio", alone or in combination, refers to alkylthioether (RS-) radicals, the term alkyl is as defined above, and sulfur is single or double. Can be oxidized. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl and the like.

As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical that has one or more triple bonds and contains 2 to 20 carbon atoms, either alone or in combination. .. In certain embodiments, the alkynyl comprises 2-6 carbon atoms. In a further embodiment, the alkynyl contains 2-4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond bonded at two positions, such as ethynylene (-C ::: C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butin-1-yl, butin-2-yl, pentyne-1-yl, 3-methylbutyne-1-yl, hexin-2-yl and the like. Unless otherwise specified, the term "alkynyl" may include an "alkynylene" group.

As used herein, the terms "amide" and "carbamoyl" refer to the amino groups described below, either alone or in combination, linked to a parent molecule moiety via a carbonyl group or vice versa. As used herein, the term "C-amide", alone or in combination, refers to the -C (O) N (RR') group, where R and R'are defined herein. Or defined by the "R" group listed in the specified details. As used herein, the term "N-amide", alone or in combination, refers to the RC (O) N (R')-group, where R and R'are defined herein. Or defined by the "R" group listed in the specified details. As used herein, the term "acylamino" includes acyl groups attached to a parent moiety via an amino group, alone or in combination. An example of an "acylamino" group is acetylamino (CH ₃ C (O) NH-).

As used herein, the term "amino", alone or in combination, refers to -NRR', where R and R'are independent of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, hetero. It can be selected from aryl, and heterocycloalkyl, any of which can be optionally substituted by itself. In addition, R and R'can combine to form heterocycloalkyl, any of which can be optionally substituted.

As used herein, the term "aryl" means a carbocyclic aromatic system comprising one, two, or three rings, alone or in combination, such a polycyclic ring. The systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthrasenyl, and phenanthryl.

As used herein, the term "arylalkenyl" or "aralkenyl" refers to an aryl group attached to a parent molecule moiety via an alkenyl group, alone or in combination.

As used herein, the term "arylalkoxy" or "aralkoxy" refers to an aryl group attached to a parent molecule moiety via an alkoxy group, alone or in combination.

As used herein, the term "arylalkyl" or "aralkyl" refers to an aryl group that, alone or in combination, is attached to a parent molecule moiety via an alkyl group.

As used herein, the term "arylalkynyl" or "aralkynyl" refers to an aryl group that is attached to a parent molecule moiety via an alkynyl group, alone or in combination.

The terms "aryl alkanoyl" or "aralkanoyl" or "aroyl" as used herein, alone or in combination, are benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyle), 4-phenylbuty. Refers to an acyl radical derived from an aryl substituted alkanecarboxylic acid such as lyl, (2-naphthyl) acetyl, and 4-chlorohydrocinnamoyle.

As used herein, the term aryloxy, alone or in combination, refers to an aryl group attached to a parent molecule moiety via oxy.

As used herein, the terms "benzo" and "benz" refer to the divalent radical C ₆ H ₄ = derived from benzene, alone or in combination. Examples include benzothiophene and benzimidazole.

The term "carbamate" as used herein can be combined with the parent molecule moiety from either the nitrogen or acid end, alone or in combination, and can be optionally substituted as defined herein. Refers to the ester of carbamic acid (-NHCOO-).

As used herein, the term "O-carbamyl" refers to -OC (O) NRR', which is a group having R and R'as defined herein, alone or in combination.

As used herein, the term "N-carbamyl" refers to the ROC (O) NR'-group with R and R'as defined herein, alone or in combination.

As used herein, the term "carbonyl", alone, comprises formyl [-C (O) H] and is a combination of -C (O) -groups.

As used herein, the term "carboxyl" or "carboxyl" refers to the corresponding "carboxylate" anion, such as in -C (O) OH or carboxylate. The "O-carboxy" group refers to the RC (O) O-group, where R is as defined herein. The "C-carboxy" group refers to the -C (O) OR group, where R is as defined herein.

As used herein, the term "cyano" refers to -CN alone or in combination.

As used herein, the term "cycloalkyl", or alternative "carbon ring," refers to saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl groups alone or in combination. Pointing to, each cyclic moiety can be a benzo-fused ring system containing 3-12 carbon atom ring members and optionally substituted as defined herein. In certain embodiments, the cycloalkyl will contain 5-7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like. As used herein, "bicyclic" and "tricyclic" are both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and polycyclic (multicentric) saturated or partially unsaturated forms. Is intended to include. The latter type of isomer is generally exemplified by bicyclo [1,1,1] pentane, camphor, adamantane, and bicyclo [3,2,1] octane.

As used herein, the term "ester" refers to a carboxy group that crosslinks two moieties bonded at a carbon atom, alone or in combination.

As used herein, the term "ether" refers to an oxy group that crosslinks two carbon atom-bonded moieties, either alone or in combination.

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine, alone or in combination.

As used herein, the term "haloalkoxy" refers to a haloalkyl group attached to a parent molecule moiety via an oxygen atom, alone or in combination.

As used herein, the term "haloalkyl" refers to an alkyl radical having the meaning defined above, in which one or more hydrogens are replaced with halogen, alone or in combination. The details include monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. The monohaloalkyl radical can have, for example, an iodine, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have more than one of the same halo atom, or a combination of different halo radicals. Examples of haloalkyl radicals are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl. , And dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF _2- ), chloroform (-CHCl-) and the like.

As used herein, the term "heteroalkyl", alone or in combination, consists of a specified number of carbon atoms and 1-3 heteroatoms selected from N, O, and S. Refers to stable linear or branched chains, or combinations thereof, including fully saturated or 1-3 degree unsaturated, N and S atoms can be arbitrarily oxidized, and N heteroatoms are arbitrarily quaternized. obtain. The heteroatom (s) can be located at any internal position of the heteroalkyl group. The maximum of two heteroatoms may be continuous, for example, _{-CH2 -} NH-OCH3.

As used herein, the term "heteroaryl", alone or in combination, is a 3- to 15-membered unsaturated heterocyclic ring, or a fused monocyclic ring in which at least one of the fused rings is aromatic, two. Refers to a cyclic or tricyclic ring system and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl will contain 1 to 4 heteroatoms as ring members. In a further embodiment, the heteroaryl comprises one or two heteroatoms as ring members. In certain embodiments, the heteroaryl will contain 5-7 atoms. The term is that the heterocyclic ring is fused with an aryl ring, the heteroaryl ring is fused with another heteroaryl ring, the heteroaryl ring is fused with a heterocycloalkyl ring, or the heteroaryl ring is fused with a cycloalkyl ring. It also includes fused polycyclic groups. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazolyl, pyranyl, frills, thienyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indrill, isoindrill, indolydinyl , Kinolyl, isoquinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, Includes tetrahydroquinolinyl, tetrazopyrrolidadinyl, tetrahydroisoquinolinyl, thienopyridinyl, pienopyridinyl, pyropyridinyl, pyrrolidinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidrill, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term "heterocycloalkyl" as used herein, and compatiblely, "heterocycle", alone or in combination, each contain at least one heteroatom as a ring member, saturated, partially unsaturated, or Completely unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic groups, each heteroatom can be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl will contain 1 to 4 heteroatoms as ring members. In a further embodiment, the heterocycloalkyl will contain one or two heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will contain 3-8 ring members on each ring. In a further embodiment, the heterocycloalkyl will contain 3-7 ring members in each ring. In yet further embodiments, the heterocycloalkyl will contain 5-6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, tertiary nitrogen ring member N-oxides, and carbocyclic condensation and benzo-fused ring systems, and both terms are also used. Also included is a system in which the heterocycle as defined herein is fused to an aryl group or an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindrill, dihydroisoquinolinyl, dihydrosinnolinyl, dihydrobenzodioxynyl, dihydro [1,3] oxazolo. [4,5-b] Pyrizinyl, benzothiazolyl, dihydroindrill, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl , Piperidinyl, thiomorpholinyl and the like. Heterocyclic groups can be arbitrarily substituted unless otherwise specified.

As used herein, the term "hydrazinyl" refers to two amino groups linked by a single bond, i.e. -NN-, alone or in combination.

As used herein, the term "hydroxy" refers to -OH alone or in combination.

As used herein, the term "hydroxyalkyl" refers to a hydroxy group attached to a parent molecule moiety via an alkyl group, alone or in combination.

As used herein, the term "imino", alone or in combination, refers to = N-.

As used herein, the term "iminohydroxy" refers to = N (OH) and = NO- alone or in combination.

The phrase "in the main chain" refers to the longest continuous or adjacent chain of carbon atoms starting at the point of attachment of a group to any one compound of the formula disclosed herein.

The term "isocyanate" refers to the -NCO group.

The term "isothiocianato" refers to the -NCS group.

The phrase "atomic linearity" refers to the longest linearity of an atom independently selected from carbon, nitrogen, oxygen, and sulfur.

As used herein, the term "lower" is meant to include ₁ to ₆ carbon atoms (ie, C1-C6 alkyl), alone or in combination, unless otherwise defined. means.

As used herein, the term "lower aryl" alone or in combination means phenyl or naphthyl, any of which may be optionally substituted as provided.

As used herein, the term "lower heteroaryl" alone or in combination is 1) a monocyclic heteroaryl containing 5 or 6 ring members, of which 1 to 4 rings. The member is a monocyclic heteroaryl, which can be a heteroatom selected from N, O, and S, or 2) a bicyclic heteroaryl, each of which is an N, O, And S means any of the bicyclic heteroaryls comprising 5 or 6 ring members containing 1 to 4 heteroatoms selected from them.

As used herein, the term "lower cycloalkyl" means monocyclic cycloalkyl having 3 to 6 ring members (ie, C ₃ -C ₆ cycloalkyl) alone or in combination. .. Lower cycloalkyls can be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "lower heterocycloalkyl" alone or in combination means a monocyclic heterocycloalkyl having 3 to 6 ring members, of which 1 to 4 are. It can be a heteroatom selected from N, O, and S (ie, C3 _{- C6} heterocycloalkyl). Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazoridinyl, piperidinyl, piperazinyl, and morpholinyl. The lower heterocycloalkyl can be unsaturated.

As used herein, the term "lower amino", alone or in combination, refers to -NRR', where R and R'are independently selected from the group consisting of hydrogen, alkyl, and lower heteroalkyl. , Any of which can be arbitrarily replaced. In addition, the lower amino groups R and R'can combine to form 5- or 6-membered heterocycloalkyls, any of which can be optionally substituted.

As used herein, the term "mercaptil", alone or in combination, refers to the RS group, where R is as defined herein.

The term "nitro" as used herein refers to -NO ₂ alone or in combination.

As used herein, the term "oxy" or "oxa" refers to -O- alone or in combination.

As used herein, the term "oxo", alone or in combination, refers to = O.

The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms have been replaced with halogen atoms.

As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms, either alone or in combination.

As used herein, the terms "sulfonate,""sulfonicacid," and "sulfonic acid", alone or in combination, when sulfonic acid is used for salt formation, the -SO _3H group and its anions. Point to.

As used herein, the term "sulfanyl" refers to -S- alone or in combination.

As used herein, the term "sulfinyl" refers to -S (O)-alone or in combination.

As used herein, the term "sulfonyl" refers to -S (O) _2- alone or in combination.

The term "N-sulfonamide" refers to the RS (= O) ₂ NR'-group with R and R'as defined herein.

The term "S-sulfonamide" refers to the -S (= O) ₂ NRR'group having R and R'as defined herein.

As used herein, the terms "thia" and "thio" refer to the -S-group or ether in which oxygen has been replaced with sulfur, alone or in combination. Oxidized derivatives of thio groups, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

As used herein, the term "thiol" refers to the -SH group alone or in combination.

The term "thiocarbonyl" as used herein comprises thioformyl-C (S) H alone and is a -C (S) -group in combination.

The term "N-thiocarbamyl" refers to the ROC (S) NR'-group with R and R'as defined herein.

The term "O-thiocarbamyl" refers to the -OC (S) NRR'group having R and R'as defined herein.

The term "thiocianato" refers to the -CNS group.

The term "trihalomethane sulfonamide" refers to an X ₃ CS (O) ₂ NR-group in which X is a halogen and has an R as defined herein.

The term "trihalomethanesulfonyl" refers to the X3 CS (O) _{2 -} group, where X is a halogen.

The term "trihalomethoxy" refers to the X ₃ CO- group, where X is a halogen.

As used herein, the term "trisubstituted silyl", alone or in combination, refers to a silicone group substituted with its three free valences in the groups listed herein under the definition of substituted amino. Point to. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein can be used in combination with any other definition to illustrate the composite structural group. By convention, the successor element of any such definition is the element that attaches to the parent part. For example, the complex group alkylamide represents an alkyl group bonded to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group bonded to the parent molecule via an alkyl group.

When a group is defined as "null", it means that the group does not exist.

The term "arbitrarily substituted" means that the precursor can be substituted or unsubstituted. When substituted, the substituent of an "arbitrarily substituted" group is one or more substituents independently selected from the following groups or a particular set of specified groups, either alone or in combination. It may include, but is not limited to: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkynyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, Aryloxy, lower alkoxyalkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarboxyester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amide, nitro, thiol. , Lower alkylthio, lower haloalkylthio, lower haloalkylthio, lower haloalkylthio, aryl, thio, sulfonate, sulfonic acid, trisubstituted silyl, N ₃ , SH, SCH ₃ , C (O) CH ₃ , CO ₂ CH ₃ , CO _2H , pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, a 5, 6 or 7 member condensation consisting of 0 to 3 heteroatoms that bond the two substituents together to form, for example, methylenedioxy or ethylenedioxy. It can form a carbocycle or a heterocycle. Groups that are optionally substituted can be unsubstituted (eg, -CH ₂ CH ₃ ), fully substituted (eg, -CF ₂ CF ₃ ), single substituted (eg, -CH ₂ CH ₂ F), or fully substituted and simple. It can be replaced at any level between the replacements (eg, -CH ₂ CF ₃ ). When a substituent is described without limitation for substitution, both substituted and unsubstituted forms are included. Substitution forms are particularly intended when the substituents are limited to being "substituted". In addition, any substituents in different sets for a particular moiety can be defined as needed, in which case any substitution is as defined and is often "arbitrarily substituted". Immediately after the phrase.

Unless otherwise defined, the term R or R'is displayed on its own and without numbering and is a portion selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl. Point and any of them can be arbitrarily replaced. It should be appreciated that such R and R'groups are optionally substituted as defined herein. All R groups (n = (1, 2, 3, ... n) in the formula, all substitutions, including R, R', and R ⁿ , whether or not the R group has a number designation. Groups, and all terms, should be understood to be independent of each other with respect to selection from the groups. Any variability, substituent, or term (eg, aryl, heterocycle, R, etc.) may be an expression or general. If it appears more than once in a structure, its definition at each appearance is irrelevant to the definition at the time of the other appearance. As such, it will be further appreciated that an asymmetric group such as -C (O) N (R)-can occupy a position in the chain of elements from either end, either carbon or nitrogen. Can be combined with the parent part.

The asymmetric center is present in the compounds disclosed herein. These centers are represented by the symbol "R" or "S", depending on the arrangement of substituents around the chiral carbon atom. It is to be understood that the present disclosure includes all stereochemical isomer forms, including diastereomers, enantiomers, and epimer forms, as well as d isomers and mono isomers, and mixtures thereof. The individual stereoisomers of the compound are separated from a commercially available starting material containing a chiral center or by preparing a mixture of enantiomer products, followed by conversion to a mixture of diastereomers, followed by separation or recrystallization, It can be synthetically prepared by a chromatographic technique, direct separation of the enantiomer on a chiral chromatography column, or any other suitable method known in the art. Certain stereochemical starting compounds are commercially available or can be made and solved by techniques known in the art. In addition, the compounds disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entogegen (E), and tsuzanmen (Z) isomers, as well as appropriate mixtures thereof. In addition, the compounds may exist as tautomers, all of which are provided by the present disclosure. Compounds containing hydroxypyridine groups may contain to varying degrees of pyridone tautomers. Both hydroxypyridine and pyridone tautomeric forms are provided by the present disclosure. Furthermore, the compounds disclosed herein can exist in non-solvate and solvate forms using pharmaceutically acceptable solvents such as water, ethanol and the like. Generally, the solvated form is considered equivalent to the non-solvated form.

The term "bond" refers to two atoms, or a covalent bond between two parts, where the atoms connected by the bond are considered to be part of a larger substructure. Bonds can be single, double, or triple unless otherwise specified. The dashed line between the two atoms in the drawing of the molecule indicates that additional bonds may or may not be present at that location.

The term "disease" as used herein is generally synonymous with the terms "disorder," "syndrome," and "condition," and is compatible with these terms (as well as medical conditions). Intended to be used, all reflect the abnormal condition of one of the human or animal bodies, or parts thereof, that impair normal function, typically distinguishing signs and symptoms. Represented by this, it results in a reduced survival or quality of life for humans or animals.

The term "combination therapy" means administration of two or more therapeutic agents to treat a therapeutic condition or disorder described herein. Such administration comprises co-administering these therapeutic agents substantially simultaneously, such as in a single capsule having a fixed ratio of the active ingredient, or in multiple separate capsules for each active ingredient. In addition, such administration also includes the continuous use of each type of therapeutic agent. In any case, the treatment regimen will provide the beneficial effect of the combination of drugs in the treatment of the conditions or disorders described herein.

The term "Des" means dihydroceramide desaturase and includes Des1 and Des2 isoforms. It should be appreciated that when Des1 regulation by a compound is referred to, the compound may also regulate other isoforms, unless specifically stated to be selective for Des1.

The term Des inhibitor (including Des1 inhibitor) is used herein and is, for example, about 100 μM or less, more typically about 50 μM or less, as measured in the Des1 cell assay generally described below. Refers to a compound that exhibits an IC ₅₀ with respect to Des activity. IC ₅₀ is the concentration of inhibitor that halves the activity of the enzyme (eg, Des). Certain compounds disclosed herein have been found to exhibit inhibition of Des. In certain embodiments, the compound exhibits an IC ₅₀ of about 10 μM or less with respect to Des, in a further embodiment the compound exhibits an IC ₅₀ of about 5 μM or less with respect to Des, and in yet further embodiments, the compound exhibits Des. In a further embodiment, the compound exhibits an IC ₅₀ of about 200 nM or less with respect to Des, and in a further embodiment, the compound exhibits an IC ₅₀ of about 100 nM or _less with respect to Des. In a further embodiment, the compound exhibits an IC ₅₀ of about 50 nM or less with respect to Des, in a further embodiment the compound exhibits an IC ₅₀ of about 25 nM or less with respect to Des, and in a further embodiment, the compound exhibits Des. Will show an _IC50 of about 10 nM or less.

The term "fibrosis" describes the development of fibrotic connective tissue as a repair response to injury or injury. When referred to herein as a disease to be treated, fibrosis means the pathological formation / deposition of excess fibrotic connective tissue in an organ or tissue that interferes with normal organ or physical function.

The phrase "therapeutically effective" is intended to limit the amount of active ingredient used in the treatment of a disease or disorder or for the effects of clinical endpoints.

The term "therapeutically acceptable" is suitable for use in contact with the patient's tissue without undue toxicity, irritation, and allergic reactions, and corresponds to a reasonable benefit / risk ratio. Refers to compounds that are effective for their intended use (or salts, prodrugs, tautomers, zwitterionic forms, etc.).

As used herein, "treat," "treatment," etc., alleviate, ameliorate, or eliminate one or more of its causes, its progression, its severity, or its symptoms. Or otherwise, it means ameliorating the disease so as to beneficially modify the disease in question. References to a patient's "treat" or "treatment" are intended to include prophylaxis. Treatment can also be proactive in nature, i.e., include prevention of disease in subjects exposed to or at risk of disease. Disease prophylaxis may involve complete protection from the disease, for example, as in the case of prevention of pathogen infection, or, for example, prevention of disease progression from pre-diabetes to diabetes. For example, disease prophylaxis does not mean complete elimination of any effect at any level associated with the disease, but instead prevents the symptoms of the disease to a clinically significant or detectable level. Can mean. Prevention of the disease can also mean prevention of progression to the later stages of the disease.

In the present disclosure, the term "radiation" is a particle or photon that has sufficient energy or is capable of producing sufficient energy through nuclear interactions to generate ionization (acquisition or loss of electrons). Means ionizing radiation including. An exemplary and preferred ionizing radiation is X-rays. Means for delivering X-rays to target tissues or cells are well known in the art. The amount of ionizing radiation required for a given cell generally depends on the nature of that cell. Means for determining an effective amount of radiation are well known in the art. As used herein, the term "effective dose" means the dose of ionizing radiation that results in increased cell damage or death.

The term "radiation therapy" refers to the use of electromagnetic or particle radiation in the treatment of tumors and includes the use of ionizing and non-ionizing radiation.

The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include domestic animals such as humans, cows, goats, sheep, pigs, and rabbits, as well as companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

The term "prodrug" refers to a compound that is more activated in vivo. The specific compounds disclosed herein may also exist as prodrugs. The prodrugs of the compounds described herein are structurally modified forms of the compounds that are readily chemically altered under physiological conditions to provide the compounds. In addition, prodrugs can be converted to compounds by chemical or biochemical methods in the Exvivo environment. For example, a prodrug can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because they may be easier to administer than the compound or parent drug in some cases. They may be biologically available, for example by oral administration, but not the parent drug. Prodrugs may have better solubility in pharmaceutical compositions than the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolysis cleavage or oxidative activation of the prodrug. An example, but not limited to, a prodrug is a compound that is administered as an ester, which is then metabolized and hydrolyzed to the active substance carboxylic acid. Further examples include peptidyl derivatives of the compound.

The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes the compounds listed above in the form of salts comprising acid addition salts. Suitable salts include salts formed of both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts can be useful in the preparation and purification of the compound in question. Basic addition salts may also be formed and are pharmaceutically acceptable.

As used herein, the term "therapeutically acceptable salt" is, as defined herein, water or oil soluble or dispersible and therapeutically acceptable, herein. Represents a salt or amphoteric ion form of a compound disclosed in. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate compound in free base form with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, L-ascorbate, asparagate, benzoate, benzenesulfonate (vesylate), bicarbonate, butyrate, etc. Kanfa salt, campha sulfonate, citrate, digluconic acid, formate, fumarate, gentisinate, glutarate, glycerophosphate, glycolate, hemisulfate, heptaneate, hexaneic acid Salt, horse urate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (icetionate), lactate, maleate, malonate, DL-mandelate , Mesitylene sulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate , Phosphate, picphosphate, pivalate, propionate, pyroglutate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, Includes glutamate, bicarbonate, paratoluenesulfonate (p-tosylate), and undecanoate. In addition, the bases in the compounds disclosed herein include chlorides, bromides of methyl, ethyl, propyl and butyl, and iodide, dimethyl, diethyl, dibutyl, and diamil sulfates, decyls, lauryls, myristyls. And can be quaternized with steryl chloride, bromide, and iodide, benzyl bromide and phenethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and oxalic acid, maleic acid, succinic acid, citric acid, etc. Contains organic acids. Salts can also be formed by coordinating compounds with alkali metals or alkaline earth ions. Accordingly, the present disclosure contemplates sodium, potassium, magnesium, calcium salts and the like of the compounds disclosed herein.

The basic addition salt reacts the carboxy group with a suitable base such as a hydroxide, carbonate, or bicarbonate of the metal cation, or with ammonia or organic primary, secondary, or tertiary amines. Can be prepared during the final isolation and purification of the compound. Treatmentally acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and tri. Butylamine, pyridine, N, N-dimethylalaniline, N-methylpiperidine, N-methylmorpholin, dicyclohexylamine, prokine, dibenzylamine, N, N-dibenzylphenethylamine, 1-ephenamine, and N, N'-di Includes non-toxic quaternary amine cations such as benzylethylenediamine. Other representative organic amines useful in the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

Salts of compounds can be made by reacting the appropriate compound in free base form with the appropriate acid.

Pharmaceutical Compositions While it is possible to administer the compounds of the present disclosure as raw chemicals, it is also possible to present them as pharmaceutical formulations. Accordingly, what is provided herein is one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, and the like. Alternatively, it is a pharmaceutical preparation comprising a solvate, one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to its recipient. The appropriate formulation depends on the route of administration chosen. Any of the well-known techniques, carriers, and excipients is suitable and can be used as understood in the art. The pharmaceutical compositions disclosed herein are any known in the art, eg, by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsification, encapsulation, encapsulation, or compression process processes. Can be manufactured by method.

The formulations include oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (skin, cheek, sublingual). , And those suitable for administration (including intraocularly), but the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulation can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Typically, these methods, along with carriers constituting one or more auxiliary components, are the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, amides, prodrugs, or solvates thereof ("" Includes the step of associating the active ingredient "). Generally, a pharmaceutical product is prepared by uniformly and intimately associating the active ingredient with a liquid carrier, a fine powder solid carrier, or both, and then, if necessary, shaping the product into the desired pharmaceutical product.

Formulations of the compounds disclosed herein may be presented as individual units such as capsules, tablets, cashiers, packets, or ampoules, each containing a predetermined amount of active ingredient.

The compounds described herein can be administered as follows.

Oral Administration The compounds of the present disclosure may be administered orally, including swallowing, and thus the compounds may enter the gastrointestinal tract or be absorbed directly into the bloodstream through the mouth, including sublingual or oral administration.

Suitable compositions for oral administration include tablets, pills, cashews, lozenges, and solid formulations such as hard or soft capsules, which may include liquids, gels, powders, or granules.

In the tablet or capsule form, the amount of drug present can be from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight.

In addition, tablets or capsules may contain disintegrants comprising from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include methyl cellulose, sodium carboxymethyl cellulose or calcium, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch and the like.

Binders suitable for use in tablets include gelatin, polyethylene glycol, sugar, rubber, starch, hydroxypropyl cellulose and the like. Suitable diluents for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch.

Surfactants and fluidizers suitable for use in tablets or capsules may be present in an amount of about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide. ..

Lubricants suitable for use in tablets or capsules may be present in an amount of about 0.1% to about 5% by weight and include calcium stearate, zinc stearate, or magnesium stearate, sodium stearyl fumarate and the like. ..

Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets are prepared by compressing the active ingredient in free-flowing form, such as powder or granules, with a suitable machine and optionally mixing with a binder, inert diluent, or lubricant, surfactant or dispersant. obtain. Molded tablets can be made by molding a mixture of powdered compounds moistened with a liquid diluent on a suitable machine. The dye or dye can be added to the tablet for identification or to characterize different combinations of active compound doses.

Liquid formulations can include emulsions, solutions, syrups, elixirs, and suspensions and can be used in soft or hard capsules. Such formulations may include pharmaceutically acceptable carriers such as water, ethanol, polyethylene glycol, cellulose, or oil. The pharmaceutical product may also contain one or more emulsifiers and / or suspensions.

The composition for oral administration can optionally be formulated with an enteric coating as immediate or controlled release, including delayed or sustained release.

In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical formulations that can be used orally include tablets, indentation capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets are prepared by compressing the active ingredient in free-flowing form, such as powder or granules, with a suitable machine and optionally mixing with a binder, inert diluent, or lubricant, surfactant or dispersant. obtain. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent on a suitable machine. The tablets may optionally be coated or nicked and may be formulated to provide a sustained release or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. The push-in capsule can contain a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally an active ingredient mixed with a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, optionally, a concentrated sugar solution may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. obtain. The dye or dye can be added to the tablet or dragee coating for identification or to characterize different combinations of active compound doses.

Parenteral administration The compounds of the present disclosure can be administered directly into the bloodstream, muscles, or internal organs by injection, eg, by bolus injection or continuous injection. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous arterial, intraperitoneal, subarachnoid space, intracranial and the like. Suitable devices for parenteral administration include syringes (including needles and needleless syringes) and injection methods. The formulation may be presented in unit dose or multidose containers, such as sealed ampoules and vials.

Most parenteral formulations are isotonic with salts, buffers, suspensions, stabilizers and / or dispersants, excipients, bacteriostatic agents, preservatives, and the blood of the recipient intended for the formulation. An aqueous solution containing an excipient containing a solute and a carbohydrate.

The parenteral preparation can also be prepared in dehydrated form (eg, by lyophilization) or in sterile non-aqueous solution. These formulations can be used with suitable vehicles such as sterile water. Solubility improvers can also be used to prepare parenteral solutions. Compositions for parenteral administration can be formulated as immediate or regulated release, including delayed or sustained release. The compound can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymer or hydrophobic material (eg, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, eg, a sparingly soluble salt. ..

The compound may be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. The injectable formulation may be presented in unit dosage form, eg, with an additional preservative, in an ampoule or multidose container. The composition can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may include pharmaceuticals such as suspending agents, stabilizers and / or dispersants. The formulation may be provided in unit dose or multi-dose containers, eg, sealed ampoules and vials, requiring only the addition of a lyophilized liquid carrier, eg, saline or lyophilized water-free water, immediately prior to use. Can be stored in powder form or in a lyophilized (lyophilized) state. Immediate injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types described above.

Aqueous and non-aqueous (oil-based) active compounds that may include an antioxidant, a buffer, a bacteriostatic agent, and a solute that makes the product isotonic with the blood of the intended recipient. Includes sterile injectable solutions, as well as aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of high concentration solutions.

In addition to the above-mentioned formulations, the compound can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymer or hydrophobic material (eg, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, eg, a sparingly soluble salt. ..

Topical administration The compounds of the present disclosure may be administered topically (eg, to the skin, mucous membranes, ears, nose, or eyes) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like. Pharmaceutically acceptable carriers for topically administered formulations can include water, alcohols, mineral oils, glycerin, polyethylene glycol and the like. Topical administration can also be performed, for example, by electroporation, iontophoresis, phonophoresis, or the like.

Typically, the active ingredient for topical administration may contain 0.001% to 10% w / w (weight) of the pharmaceutical product. In certain embodiments, the active ingredient is up to 10% w / w, less than 5% w / w, 2% w / w-5% w / w, or 0.1% -1% w / w of the formulation. Can include.

Compositions for topical administration can be formulated as immediate or regulated release, including delayed or sustained release.

The specific compounds disclosed herein can be administered topically, ie by non-systemic administration. This includes applying the compounds disclosed herein to the outside of the epidermis or oral cavity, and instilling such compounds into the ears, eyes, and nose so that the compounds do not significantly enter the bloodstream. ..
In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Suitable formulations for topical administration include gels, liniments, lotions, creams, ointments, or pastes that are liquid or semi-liquid preparations suitable for penetration into the inflamed area through the skin, and eyes, ears, or nose. Contains a drop suitable for administration to. The active ingredient for topical administration may include, for example, 0.001% to 10% w / w (weight) of the pharmaceutical product. In certain embodiments, the active ingredient may contain up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the pharmaceutical product.

Rectal, Oral, Sublingual Administration Suppositories for rectal administration of the compounds of the present disclosure are cocoa, which dissolves the active agent in the rectum, solid at room temperature but liquid at rectal temperature, thus releasing the drug. It can be prepared by mixing with a suitable non-irritating excipient such as butter, synthetic mono, di, or triglyceride, fatty acid, or polyethylene glycol.

For oral or sublingual administration, the composition may be in the form of tablets, lozenges, pastils, or gels formulated by conventional methods. Such compositions may contain active ingredients on a flavor basis such as sucrose and acacia or tragacanth.

The compound may include conventional suppository bases such as, for example, cocoa butter, polyethylene glycol, or other glycerides in rectal compositions such as suppositories or retention enemas.

Administration by Inhalation For administration by inhalation, the compound may be conveniently delivered from a nebulizer, nebulizer pressure pack, or other convenient means of delivering an aerosol spray. Pressurized packs may contain suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. For pressurized aerosols, the dosage unit may be determined by providing a valve for delivering the measured amount. Alternatively, for administration by inhalation or blowing, the compounds according to the present disclosure may take the form of a dry powder composition, eg, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be provided in unit dosage form, for example in capsules, cartridges, gelatin, or blister packs, from which the powder may be administered using an inhaler or injector.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention can be prepared by any of the pharmaceutically well known techniques, such as effective formulations and administration procedures. A preferred unit-dose formulation comprises the active ingredients listed below, or the active ingredient of the appropriate fraction thereof.

In particular, in addition to the above-mentioned components, the above-mentioned preparation may contain other conventional agents in the art in consideration of the type of the preparation in question, for example, those suitable for oral administration may contain a flavoring agent. Please understand that.

The compound can be administered orally or by injection at a dose of 0.1-500 mg / kg per day. The dose range for adult humans is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in separate units conveniently contain one or more compounds that are effective at such doses or as multiples thereof, such as 5 mg to 500 mg, usually about 10 mg to 200 mg. May include.

The amount of active ingredient that can be combined with the carrier material to make a single dosage form will vary depending on the host being treated and the particular mode of administration.

The compounds can be administered in various modes, eg, orally, topically, or by injection. The exact amount of compound administered to the patient is the responsibility of the attending physician. Specific dose levels for any particular patient are treated with activity, age, weight, general health, gender, diet, duration of administration, route of administration, rate of excretion, drug combination, treatment of the particular compound used. It will depend on a variety of factors, including the exact disorder and the severity of the indication or condition being treated. In addition, the route of administration can vary depending on the condition and its severity. The above considerations regarding effective formulations and dosing procedures are well known in the art and are described in standard textbooks.

Therapeutic Methods The present disclosure provides compounds and pharmaceutical compositions that inhibit Des activity and is therefore useful in the treatment or prevention of Des-related disorders. The compounds and pharmaceutical compositions of the present disclosure inhibit Des and are therefore useful in the treatment or prevention of various disorders associated with Des1.

Metabolic Disorders In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful in the treatment or prevention of metabolic disorders.

In some embodiments, the metabolic disorder is selected from metabolic syndrome, diabetes, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, non-alcoholic steatosis, obesity, and insulin resistance. ..

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful in the treatment or prevention of impaired lipid accumulation. In some embodiments, the impaired lipid accumulation is selected from Fabr's disease, Niemann-Pick's disease, Fabry's disease, Krabbe's disease, Gaucher's disease, Tay-Sachs disease, and allogeneic leukodystrophy.

In some embodiments, the compounds and pharmaceutical compositions show efficacy for conditions selected from dyslipidemia, type II diabetes, atherosclerosis, obesity, cardiovascular disease, and liver disease. obtain.

In some embodiments, the compounds and pharmaceutical compositions may be effective against liver disease selected from NASH and NAFLD.

In some embodiments, the compounds and pharmaceutical compositions may be effective against insulin resistance.

In some embodiments, the compounds and pharmaceutical compositions may be effective against hyperglycemia.

Cardiovascular Disorders In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of atherosclerosis, including coronary and peripheral vascular disease, hypertension and myocardial disease.

In some embodiments, the compounds and pharmaceutical compositions may be useful in the treatment of atherosclerosis.

Cystic Fibrosis In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of cystic fibrosis. Various studies have included sphingolipids, especially ceramides, in corresponding mouse models of cystic fibrosis, including human lungs with cystic fibrosis, as well as mice with gene disruption of cystic fibrosis transmembrane conduction regulators. Has been shown to accumulate. This accumulation is associated with inflammation, increased susceptibility to bacterial infections (Grassme et al. 2013 Ceramide in cystic fibrosis. Handb. Exp. Pharmacol. 216, 265-274), and pulmonary fibrosis (Ziobro et al. 2013 Ceramide). It has been shown to cause in cystic fibrosis.Biochem.Biophys.Res.Commun.434,705-709).

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful in the treatment or prevention of autoimmune or inflammatory disorders, including acute and chronic inflammatory diseases.

Inflammatory conditions include, but are not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative arthritis, systemic erythematosus, juvenile arthritis, acute rheumatoid arthritis, enteric arthritis, and neuropathy arthritis. , Arthritis including subtypes and related conditions such as psoriatic arthritis, and purulent arthritis, osteoporosis, arthritis, synovial arthritis, and other related bone and joint disorders, reflux esophagitis, diarrhea, inflammation Gastrointestinal disorders such as gonad disease, Crohn's disease, gastric inflammation, irritable intestinal syndrome, ulcerative arthritis, acute and chronic inflammation of the pancreas, lung inflammation associated with viral infections and cystic fibrosis, psoriasis, eczema, burns, sunburn , Arthritis (such as arthritis, atopic dermatitis, and allergic dermatitis), and skin-related conditions such as urticaria, pancreatitis, hepatitis, pruritus, and leukoplakia. In addition, the compounds of the invention are also useful in organ transplant patients, either alone or in combination with conventional immunomodulators. Autoimmune diseases are often also classified as inflammatory diseases.

Autoimmune diseases include Crohn's disease, ulcerative colitis, dermatomyositis, dermatomyositis, type 1 diabetes, Good Pasture syndrome, Graves' disease, Gillan Valley syndrome (GBS), autoimmune encephalomyelitis (AE), and Hashimoto's disease. , Idiopathic thrombocytopenic purpura, erythematosus, mixed connective tissue disease, multiple sclerosis (MS), severe myasthenia, narcholepsy, vasculitis vulgaris, malignant anemia, psoriasis, psoriatic arteritis, polymyositis, Includes primary biliary cirrhosis, rheumatoid arthritis (RA), Schegren's syndrome, dermatomyositis, temporal arteritis (also known as "giant cell arteritis"), vasculitis, and Wegener's granulomatosis. ..

In some embodiments, the autoimmune or chronic inflammatory disease is arthritis, polysclerosis, psoriasis, Crohn's disease, inflammatory bowel disease, urticaria, Graves' disease and Hashimoto's thyroiditis, ankylosing spondylitis, and cysts. Selected from sexual fibrosis.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have disease-modifying antirheumatic drug (DMARD) activity. In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used in the treatment of rheumatoid arthritis. In certain additional embodiments, treatment of rheumatoid arthritis with the compounds and pharmaceutical compositions of the present disclosure includes analgesics (including conventional NSAIDs and COX2 selective inhibitors), steroids, methotrexate, gold salts, hydroxychloroquines, PAD4. Includes co-administration of an inhibitor, sulfasalazine, reflunomide, anti-TNFα, Janus kinase inhibitor, abatacept, rheuximab, and another agent selected from anaquina.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are fingolimod, sphingosine-1-phosphate receptor regulators, terifluonomid, dimethyl fumarate, PAD4 inhibitors, anti-CD20 mAb, anti-CD52 mAb, natalizumab, and the like. When co-administered with glatiramer acetate and a therapeutic agent selected from interferon-β, it may have synergistic activity against multiple sclerosis.

In some embodiments, the autoimmune disease inflammatory disease is autoimmune arthritis.

In some embodiments, the autoimmune disease inflammatory disease is rheumatoid arthritis.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are analgesics (including conventional NSAIDs and COX2 selective inhibitors), steroids, methotrexate, gold salts, hydroxychloroquins, PAD4 inhibitors, sulfasalazines, reflunomides. , Anti-TNFα, Janus kinase inhibitor, abatacept, rituximab, and may have synergistic activity against arthritis when administered in combination with a therapeutic agent selected from Anakina.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of cardiovascular disease. In some embodiments, the cardiovascular disease is selected from atherosclerosis, hypertension, and cardiomyopathy.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of ischemic / reperfusion injury. In some embodiments, the ischemic / reperfusion injury is an organ transplant, acute renal injury, cardiopulmonary bypass, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, surgical resection and reconstructive surgery, appendages or other. It occurs in rejoining of body parts, skin transplants, or trauma.

For example, proliferative disorders such as cancer In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of cancer.

In some embodiments, the cancer is leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colon rectal cancer), rectal cancer, bladder cancer, lung cancer (non-small cells). Lung cancer, lung adenocarcinoma, lung squamous epithelial cancer), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, bile sac cancer, bile duct cancer, esophageal cancer, kidney Cell cancer, thyroid cancer, head and neck squamous epithelial cancer (head and neck cancer), testis cancer, endocrine cancer, adrenal cancer, pituitary cancer, skin cancer, soft tissue cancer Cancer, vascular cancer, brain cancer, nerve cancer, eye cancer, medullary cancer, mesopharyngeal cancer, hypopharyngeal cancer, cervical cancer, and uterus Cancer, gliuloblastoma, medullary blastoma, stellate cell tumor, glioma, meningitis, gastrinoma, neuroblastoma, melanoma, myelodystrophy syndrome, and sarcoma.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are effective against tumor growth, angiogenesis, and chemical resistance, potentially by direct cytotoxicity, including induction of apoptosis. Or indirectly, tumor killing can be promoted either by enhancing the tumor killing ability of the immune system.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer when co-administered with an immune checkpoint inhibitor.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are cancer when co-administered with a monoclonal antibody of interest to a target selected from PD1, PD-L1, CTLA-4, CD47, and OX40. Can have synergistic activity against.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are cancer when co-administered with a small molecule of interest to a target selected from indoleamine-2,3-dioxygenase 1 and arginase-1. May have synergistic activity against.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of fibrosis and related diseases. Fibrosis is a pathological condition with excessive extracellular matrix production of connective tissue. As a result, tissue dysfunction and organ failure may be included.

In some embodiments, fibrosis affects sites selected from lung, kidney, liver, heart, skin, and connective tissue.

In some embodiments, fibrosis is in the lungs, such as pulmonary fibrosis or cystic fibrosis, liver, such as liver cirrhosis, heart, such as atrial fibrosis, endocardial myocardial fibrosis due to myocardial infarction, brain, eg. Intestines such as glial scars, renal fibrosis due to diabetic nephropathy, bile sac fibrosis, skin or cutaneous fibrosis such as sclerosis, hypertrophic scars and keroids, myeloid fibrosis due to myeloid fibrosis, Crohn's disease It can be fibrosis, or some other wound, in this case referred to as a scar. Fibrosis is also a complication of joint fibrosis, dupuytran contraction, mediastinal fibrosis, myeloid fibrosis, Peylony's disease, renal systemic fibrosis, progressive massive fibrosis, coal worker dust pneumonia, later. It can be selected from peritoneal fibrosis, scleroderma, systemic sclerosis, and adhesive sclerosis, as well as abdominal adhesions secondary to abdominal surgery.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to prevent, treat, or ameliorate a heart attack.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to treat various types of congestive heart failure. In certain additional embodiments, congestive heart failure is secondary to ischemia. In certain additional embodiments, congestive heart failure is associated with a disorder selected from diabetes, obesity, and lipotoxicity. In certain further embodiments, the treatment of congestive heart failure with the compounds and pharmaceutical compositions of the present disclosure comprises angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-adrenaline receptor blockers. Includes co-administration of other agents selected from (including carvesilol), diuretics (including furosemide), aldosterone antagonists (including eplerenone), inotropes (including mirinone), guanylate cyclase inhibitors, and digoxin.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used in the treatment of renal disease. In certain further embodiments, the renal disease is selected from diabetic renal disease and nephropathy. In certain additional embodiments, treatment of kidney disease with the compounds and pharmaceutical compositions of the present disclosure comprises co-administration of a standard therapeutic agent. In certain additional embodiments, standard therapeutic agents include ACE inhibitors, angiotensin receptor blockers (ARBs), cholesterol-lowering agents (including statins and / or PCSK9 inhibitors), and calcium phosphate levels for bone health. It is selected from the drugs to be managed (including ceveramar).

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to treat sarcopenia. In certain additional embodiments, the pathogenesis of sarcopenia is selected from aging, chronic kidney disease, malignancies, and chemotherapy. In certain additional embodiments, treatment of sarcopenia with the compounds and pharmaceutical compositions of the present disclosure includes testosterone, selective androgen receptor regulators, grelin agonists, myostatin antibodies, activin IIR antagonists, ACE inhibitors, beta antagonists, and Includes co-administration of another drug selected from fast skeletal muscle troponin activators.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to prevent, treat, or ameliorate neurodegenerative diseases. Elevated ceramide levels are often found in association with various neurodegenerative diseases.

In some embodiments, the neurodegenerative diseases include Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Levy's body disease, spinal muscular ataxia, Friedrich's ataxia, and Selected from spinal muscular ataxia.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to treat Alzheimer's disease. In certain additional embodiments, the compounds and pharmaceutical compositions of the present disclosure may have disease modifying activity. In certain additional embodiments, the compounds and pharmaceutical compositions of the present disclosure may provide symptom relief. In certain further embodiments, treatment of Alzheimer's disease with the compounds and pharmaceutical compositions of the present disclosure comprises co-administration of a cholinesterase inhibitor and another agent selected from memantine.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against neurodegenerative diseases when co-administered with a therapeutic agent selected from cholinesterase inhibitors and memantine.

In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against AL when co-administered with a second therapeutic agent for ALS. In certain embodiments, the second therapeutic agent for ALS is selected from riluzole and edabalon.

Combinations and Combination Therapy The compounds of the invention can be used alone or in combination with other pharmaceutically active compounds to treat conditions such as those described above. The compounds of the invention (s) and other pharmaceutically active compounds (s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. Accordingly, in one embodiment, the invention is a method of treating a condition by administering to a subject a therapeutically effective amount of one or more compounds of the invention and one or more additional pharmaceutically active compounds. include.

In another embodiment, a pharmaceutical composition comprising one or more compounds of the invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier is provided.

In another embodiment, one or more additional pharmaceutically active compounds are metformin, an inhibitor of HMG-CoA reductase, an inhibitor of a sodium / glucose cotransporter, fibrato, an omega-3 fatty acid, a glucagon-like peptide. -1 analogs and glucagon-like peptides-1 receptor agonists (eg, PF-06882961), FXR agonists (eg, obeticolic acid, INT-767, GS-9674, tropifyxol, MET409, EDP-305), LXR ligands. , PPAR agonist (eg Elafibranner), Vitamin E, FGF19 analog (eg NGM-282), FGF21 analog (eg BMS-986036), fibroblast growth factor receptor 1c-beta-croto agonist (Eg, NGM-313), acetyl CoA carboxylase inhibitors (eg, GS-0976, PF-05221304, MK4074), stearoyl CoA desatase-1, inhibitors, CCR2 / CCR5 antagonists (eg, senicribiroc), ketohexokinases. Inhibitors (eg, PF-0665919), diacylglycerol O-acyltransferase 2 inhibitors (eg, PF-06865571), ASK1 inhibitors (eg, theronseltibu, SRT-015), thyroid hormone receptor-β. Agonists (eg, MGL-3196, MGL-3745, VK2809), dipeptidylpeptidase-4 inhibitors (eg, evoglycin), stearoyl-CoA desatase-1 inhibitors (eg, alamcol), AOC3 inhibitors (Eg, BI 1467335), Caspase inhibitor (eg, Emricasan), Galectin-3 inhibitor (eg, GR-MD-02), Enteral sodium bile acid transporter inhibitor (eg, Bolixibat), P2Y13 receptor It is selected from the group consisting of anti-metabolizing agents, including body agonists (eg, CER209), DUR-928, DS102, and butanoic acid.

Additional non-limiting examples of possible combination therapies include the use of the compounds disclosed herein and at least one other agent selected from the group comprising: a) insulin, insulin. Anti-diabetic agents such as derivatives and mimetics, sulfonylureas such as insulin secretagogues such as glypidide, glybrid, and amaryl, insulin-secreting sulfonylurea receptor ligands such as meglitinide such as nateglinide and repaglinide, PTP-112 and the like. Insulin sensitizers such as the protein tyrosine phosphatase-1B (PTP-1B) inhibitor, GSK3 (glycogen synthase) such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445. Kinases-3) Inhibitors, RXR ligands such as GW-0791 and AGN-194204, sodium-dependent glucose cotransport inhibitors such as empaglifrosin, canaglyfrosin, dapaglifrosin, T-1095, glycogen phosphorylase A such as BAY R3401 Inhibitors, biguanides such as metformin, alpha-glucosidase inhibitors such as acarbose, GLP-1 (glucagon-like peptide-1) such as exendin-4 and mimetics of GLP-1, GLP-1 analog analogs, Januvia, DPPIV (dipeptidylpeptidase IV) inhibitors such as galvas, onglyza, DPP728, LAF237 (Example 1 of bildaglycin-WO 00/34241), MK-0431, saxagliptin, GSK23A, AGE breakers, pioglitazone or rosiglitazone. Derivatives (glitazones), as well as non-glitazone-type PPARdelta agonists such as GI-262570, b) 3-hydroxy-3-methyl-glutarylcoenzyme A (HMG-CoA) reductase inhibitors such as lobastatin, pitabastatin, simbatatin. , Pravastatin, Seribastatin, Mevastatin, Verostatin, Fluvastatin, Dalvastatin, Atrubastatin, Losvastatin and Rivasstatin and other lipid-lowering agents, Squalene synthase inhibitors, FXR (farnesoid X receptor) and LXR (liver X receptor) ligands, PCSK9 antagonists , For example, allilokumab and evolocumab, cholesterol absorption Inhibitors such as ezetimib, bile resin, eg cholestiramine, choleseverum, fibrato, nicotinic acid, and aspirin, c) fentermin, leptin, bromocryptin, dexanthamine, amphetamine, fenfluramine, dexfenfluramine, thibutramine. , Orlistat, dexfenfluramine, mazindole, fentermine, fendimethrazine, diethylpropion, fluoroxetine, bupropion, topiramate, benthethylpropitamin, diethylpropion, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine, or cannabinoid antagonists, etc. Anti-obesity or appetite regulators, d) antihypertensive agents, such as loop diuretics such as etaclinic acid, frosemide, and tolsemide, thiazide derivatives, diuretics such as chlorothiazide, hydrochlorothiazide, amylolide, benazepril, captopril, enalapril, fosinopril, Angiotensin converting enzyme (ACE) inhibitors such as lisinopril, moexipril, perinodopril, quinapril, lamipril, trandrapril, Na-K-ATPase membrane pump inhibitors such as digoxin, neutral endopeptidase (NEP) inhibitors, eg Thiorphan, terteo-thiolphan, SQ29072, ECE inhibitors such as ACE / NEP inhibitors such as SLV306, omapatrilate, sanpatrilate, and fasidtril, candesartan, eprosartan, ilbesartan, losartan, tenisartan, balsartan, especially balsartan. Acceptance of renin inhibitors such as angiotensin n antagonist, aliskilen, tellraquilene, ditecylene, RO 66-1132, RO-66-1168, acebutrol, atenolol, betaxolol, bisoprolol, metoprol, carvegilol, nadrol, proplanolol, sotalol, timolol, etc. Cardiotonic agents such as body blockers, digoxin, dobutamine, millinone, calcium channel blockers such as amlogipin, beprizil, zyrthiazem, ferrodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil, aldosterone receptor antagonists, and aldosterone synthase inhibitors, e ) HDL increasing compounds, f) ezetimib and KT6 Cholesterol absorption modifiers such as -971, g) Apo-Al analogs and mimetics, h) thrombin inhibitors such as xymelagatran, aldosterone inhibitors such as anastrazole, fadrazol, and eplerenone, such as aspirin. Inhibitors of platelet aggregation, as well as clopidogrel heavy sulfate.

In another embodiment, one or more additional pharmaceutically active compounds are anticancer agents including chemotherapeutic agents, alkyl sulfonates such as thiotepa and cyclophosphamide, busulfane, improsulfan, piposulfan, etc. Aziridines such as benzodepa, carbocon, methotrexate, and uredopa, altretamine, triethylene melamine, triethylene phosphate amide, ethyleneimine and methylamelamine, including triethylene thiophosphate amide and trimethylol melamine, chlorambusyl, chlornafazine, cyclophosphamide. Famide, estramstin, cyclophosphamide, methotrexate, mechloretamine hydrochloride, melfaran, novemubitin, phenesterin, predonimustin, trophosphamide, uracilmustide and other nitrogen mustards, carmustin, chlorozotocin, fotemstin, romustin, nimustin Synomycin, Actinomycin, Autoramycin, Azaseline, Breomycin, Cactinomycin, Calicaremycin, Carabicin, Caminomycin, Cardinophylline, Chromomycin, Dactinomycin, Daunorbisin, Detorbisin, 6-diazo-5-oxo- L-norleucine, doxorubicin, epirubicin, esorbicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, pepromycin, porphyromycin, puromycin, keramicin, rodeviclin, strepsino, strepsino, strepsino, sorbicin, etc. , Anti-metabolizers such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate, purin analogs such as fludalabine, 6-mercaptopurine, thiamypurin, thioguanine; ancitabine, Pyrimidin analogs such as azacitidine, 6-azauridine, carmofur, citarabin, dideoxyuridine, doxiflulysine, enocitabine, floxuridine, 5-FU, androgen such as carsterone, dromosterone propionate, epithiostanol, mepitiostane, testlactone. , Anti-adrenal such as aminoglutetimid, mitotan, trilostane, folic acid supplement such as floric acid, acegraton, aldphosphamide glycoside; Minolebric acid, amsacrine; Bestlabcil, Visantren, Edatraxate, Desosamine, Demecorcin, Diazicon, Ephlomitin, Elliptinium acetate, Etoposide, Gallium nitrate, Hydroxyurea, Lentinan, Ronidamine, Mitoxanrone, Mitoxantrone, Mopidamole, Nitraclin, Pentostatin , Pirarubicin, Etoposide, 2-Ethylhydrazide, Procarbazine, Razoxane, Sizophyllan, Spirogermanium, Tenazonic acid, Triazicon, 2,2', 2 "-Trichlorotriethylamine, Urethane, Vincristine, Dacarbazine, Manomustin, Mitobronitol, Mitoxantrone, Pipobroman, Platinum and platinum coordination complexes such as citocin arabinoside (Ara-C), cyclophosphamide, thiotepa, taxoids such as paclitaxel and docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin and carboplatin, Vinblastine, Etoposide (VP-16), Iphosphamide, Mitomycin C, Mitoxantrone, Vincristine, Vinolerubin, Navelvin, Novantron, Teniposide, Daunomycin, Aminopterin, Xeloda, Ivandronate, CPT11, Topoisomerase inhibitor, Difluoromethylornithine (DMFO) ), Etoposide acid, esperamicin, capecitabine, and any of the above pharmaceutically acceptable salts, acids, or derivatives.

Chemotherapeutic agents also include, for example, tamoxifen, laroxifene, aromatase inhibitory 4 (5) -imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, onapriston, tremiphen, and flutamide, anti-estrogen, selective. Includes both estrogen receptor regulators and selective estrogen receptor degradants), and anti-androgen such as flutamide, niltamide, bicartamide, leuprolide, and goseleline, as well as pharmaceutically acceptable salts of any of the above. Also includes anti-hormonal agents that act to regulate or inhibit hormonal effects on tumors such as acids, or derivatives. In certain embodiments, combination therapy comprises the administration of hormones or related hormonal agents.

Chemotherapeutic agents also include signal transduction inhibitors (STIs). The term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. The signaling inhibitors (STIs) of the present invention include (i) bcr / abl kinase inhibitors (eg, GLEEVEC), (ii) epidermal growth factor (EGF) receptor inhibitors, including antibodies. iii) her-2 / neu receptor inhibitors (eg, HERCEPTIN), (iv) Akt family kinases or inhibitors of the Akt pathway (eg, rapamycin), (v) cell cycle kinase inhibitors (eg, flavopyridol and). Palbociclib), (vi) phosphatidylinositol kinase inhibitors, (vii) selective estrogen receptor regulators (eg, tamoxiphene), (viii) selective estrogen receptor-degrading substances (eg, fullbest), (ix) selective Includes androgen receptor regulators (eg, enzaltamide, appaplutamide), (x) kinase inhibitors (eg, bevasizumab, S sutent).

Chemotherapeutic agents are also checkpoint inhibitors (eg, anti-PD1, anti-PDL1, anti-CTLA4 antibodies), as well as anti-GITR, anti-OX40, and anti-CD47 antibodies, IDO1 inhibitors, arginase-1 inhibitors, glucocorticoid receptors. Includes a variety of immunomodulators, including inhibitors, regulatory T cell inhibitors, and other immunomodulators, including bone marrow-derived suppressor cell inhibitors.

In another embodiment, one or more additional pharmaceutically active compounds are steroids, methotrexate, sulfasalazine, gold salts, and inhibitors of anti-TNF, anti-IL1, anti-IL6, and NLRP3 inframasomes, and Janus. It is selected from the group consisting of disease-modifying antirheumatic drugs (DMARD), including kinase inhibitors.

In another embodiment, one or more additional pharmaceutically active compounds are interferon-beta 1a, interferon-biobeta 1b, glatiramer acetate, mitoxanthrone, fingolimod, terifluonomido, dimethyl fumarate, anti-alpha 4 integulin. It is selected from the group consisting of multiple sclerosis agents, including monoclonal antibodies, anti-CD52 monoclonal antibodies, anti-CD25 monoclonal antibodies, and anti-CD20 monoclonal antibodies.

In another embodiment, one or more additional pharmaceutically active compounds are selected from the group consisting of enzyme replacement therapy. Enzyme replacement therapy may include, for example, recombinant human acid ceramidase.

In another embodiment, one or more additional pharmaceutically active compounds are pancreatic enzyme supplements, multivitamins, mucolytic agents, antibiotics, bronchial dilators, anti-inflammatory agents, insulin, bisphosphonates, antifibrotic agents. It is selected from the group consisting of (eg, pirfenidone, nintedanib), N-acetylcysteine, ivacuffter, and lumacuffter / ivacuffter.

In another embodiment, one or more additional pharmaceutically active compounds are donepezil, galantamine, rivastigmin, memantine, lysole, levodopa / carbidopa, pramipexol, ropinilol, rotigotine, selegiline, apomorphin, selegiline, selegiline, It is selected from the group consisting of entacapone, tolcapone, benztropin, trihexyphenidyl, amantadine, tetrabenazine, haloperidol, selegiline, quetiapine, levetilasetam, chronazepam, and edarabon.

The Des inhibitor compounds and compositions described herein are also optionally used in combination with other therapeutic reagents selected for their therapeutic value for the condition being treated. In general, the compounds described herein, and in embodiments where combination therapy is used, the other agents do not need to be administered in the same pharmaceutical composition, due to different physical and chemical characteristics. It is optionally administered by different routes. Initial doses are generally given according to established protocols, then the dosage, mode of administration, and duration of administration are subsequently modified based on the observed effects. In certain cases, it is appropriate to administer the Des1 inhibitor compound described herein in combination with another therapeutic agent. As an example, the therapeutic efficacy of a Des1 inhibitor is enhanced by the administration of another therapeutic agent (including a therapeutic regimen) that also has therapeutic benefits. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply the addition of the two therapeutic agents, or the patient experiences enhanced (ie, synergistic) benefits. It can be either. Alternatively, if the compounds disclosed herein have side effects, it may be appropriate to administer an agent to reduce the side effects, or the therapeutic efficacy of the compounds described herein is. , Can be enhanced by administration of an adjuvant.

The therapeutically effective dosage varies when the drug is used in combination with treatment. Methods for experimentally determining therapeutically effective doses of drugs and other drugs for use in combination therapy regimens are documented methodologies. Combination therapy further includes periodic therapy that starts and stops at various times to support clinical management of the patient. In any case, the plurality of therapeutic agents, one of which is the Des inhibitor disclosed herein, may be administered in any sequence or simultaneously. When simultaneous, multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (as an example only, as either a single pill or two separate pills). ).

In some embodiments, one of the therapeutic agents is given in multiple doses, or both are given in multiple doses. If not simultaneous, the timing between multiple doses will vary arbitrarily from more than 0 weeks to less than 12 weeks.

In addition, the combination method, composition, and formulation are not limited to the use of only two agents, and the use of multiple therapeutic combinations is also envisioned. It is understood that the dosing regimen for treating, preventing, or ameliorating a condition requiring palliative (s) may be voluntarily modified according to a variety of factors. These factors include the disability that the subject is affected by, as well as the subject's age, weight, gender, diet, and medical condition. Therefore, in some embodiments, the dosing regimens actually used will vary widely and therefore deviate from the dosing regimens described herein.

The pharmaceutical agents constituting the combination therapies disclosed herein are optionally in combination or separate dosage forms intended for substantially simultaneous administration. The agents constituting the combination therapy are optionally administered continuously, and any of the agents is administered by a regimen that requires a two-step administration. The two-step dosing regimen optionally requires continuous administration of the active agent or separate administration of the active agent separately. The time between multiple dosing steps ranges from minutes to hours, depending on the characteristics of each drug such as drug efficacy, solubility, bioavailability, plasma half-life, and kinetic profile.

In another embodiment, Des inhibitors are optionally used in combination with procedures that provide additional benefits to the patient. Des inhibitors and any additional therapies are optionally administered before, during, or after the onset of the disease or condition, and the timing of administration of the composition comprising the Des inhibitor varies in some embodiments.
Thus, for example, Des inhibitors are used as prophylactic agents and are continuously administered to subjects who are prone to develop a condition or condition in order to prevent the development of the condition or condition. Des inhibitors and compositions are optionally administered to the subject during or as soon as possible after the onset of symptoms. Although embodiments of the present invention have been described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, modifications, and substitutions will occur to those skilled in the art without departing from the present invention. It should be appreciated that in some embodiments of the invention, various alternatives to the embodiments described herein are used in practicing the invention.

Compound Synthesis The compounds of the present disclosure can be prepared using the general synthetic schemes and methods exemplified in the experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be restricted. The starting materials used to prepare the compounds of the present disclosure are either commercially available or can be prepared using conventional methods known in the art.

List of abbreviations Ac ₂ O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = Aqueous; Bu ₃ SnH = Tributyltin hydride; CD ₃ OD = Deuterated methanol; CDCl ₃ = Deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo [5.4] .0] Undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = deuterated di-isobutylaluminum; DIEA = DIPEA = N, N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide; DMSO-d ₆ = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC. HCl = EDCI. HCl = 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride; Et ₂ O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = time; HATU = 2- (1H-7-azabenzo) Triazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate acetonitrileamino; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; LAH = hydrogenation Aluminum lithium; LiHMDS = lithium bis (trimethylsilyl) amide; MeCN = acetonitrile; MeOH = methanol; MP carbonate resin = macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = methyl chloride; MTBE = methyl tertiary butyl ether; MW = microwave irradiation N-BuLi = n-butyllithium; NaHMDS = sodium bis (trimethylsilyl) amide; MeOH = sodium methoxyd; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N- Methyl-2-pyrrolidone; Pd (Ph ₃ ) ₄ = tetrakis (triphenylphosphine) palladium (0); Pd ₂ (dba) ₃ = tris (dibenzilidenacetone) dipalladium (0); PdCl ₂ (PPh ₃ ) ₂ = Bis (triphenylphosphine) palladium (II) dichloride; PG = protecting group; preparative HPLC = preparative high-speed liquid chromatography; PyBop = (benzotriazole-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate; Pyr = Pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2', 6'-diisopropoxybiphenyl; sat. = Saturated; ss = saturated solution; t-BuOH = tert-butanol; T3P = propylphosphonic acid anhydride; TBS = TBDMS = tert-butyldimethylsilyl; TBSCl = _TBDMSCl = tert-butyldimethylchlorosilane; TEA = Et 3N = Triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic acid anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl.

General Synthetic Methods for Preparing Compounds The following schemes can generally be used to carry out the present invention.

Example 1 can be synthesized using the following general synthetic procedure described in Scheme I. Amine 101 is converted to acid chloride 102 using triphosgene in the presence of a base elsewhere herein and abbreviated as (COCl ₂ ) ₃ . The acid chloride is then reacted with arylamine 103 in the presence of a base to give urea 103. As used herein and elsewhere, the formula H2N _- Ar-OTBS of 103 represents an aryl compound substituted with both _NH2 and OTBS groups. Formula 103 comprises, for example, 4-[(tert-butyldimethylsilyl) oxy] aniline and 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine. In the final step, the TBS group is removed with either acid or fluoride to give 105.

Examples 2-39 can be synthesized using the following general synthetic procedure described in Scheme II. In the first step, amine 201 is directly reacted with 4-fluorophenylcarbamate having formula 202 in the presence of a base to give urea 203. As used herein and elsewhere, the formula of carbamate 202 comprises an arylamino moiety substituted with an OTBS group. Formula 202 is, for example, 4-fluorophenyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate and 4-fluorophenyl N- [4-[(tert-butyldimethylsilyl)). Contains oxy] phenyl] carbamate. In the second step, the TBS group is removed with either acid or fluoride to give 204.

Example 40 can be synthesized using the following general synthetic procedure described in Scheme III. In the first step, the alkyl isocyanate 301 is reacted with the arylamine 103 as defined in Scheme I to give the urea 302. The TBS group is removed in the second step by treatment with any acid of the fluoride ion to give 303.

Examples 41-42 can be synthesized using the following general synthetic procedures described in Scheme IV. In the first step, the acid chloride 401 is reacted with the arylamine 103 as defined in Scheme I to give the carbamate 402. The TBS group is removed in the second step by treatment with any acid of the fluoride ion to give 403.

Examples 43-44 can be synthesized using the following general synthetic procedure described in Scheme V. Alcohol 501 is reacted with arylamine 103 in the presence of triphosgene and base as defined in Scheme I to give carbamate 502. In the final step, the TBS group is removed with either acid or fluoride to give 503.

Examples 45-52 can be synthesized using the following general synthetic procedures described in Scheme VI. Synthesis begins with the amine / carbamate 601 whose "L" moiety is the linking group. In some embodiments, 601 is 1-Boc-piperazine. In some embodiments, 601 is 1-Cbz-piperazine. In some embodiments, 601 is 3- (BocNH) -piperidine. In some embodiments, 601 is 4- (BocNH) -piperidine.

The amine / carbamate 601 is then reacted with arene 602 to give the arylamine substitution product 603. In certain embodiments, arene 602 is replaced with an electron _- removing group that facilitates a direct SNA reaction. In certain embodiments, the substitution reaction is assisted by the presence of a metal catalyst.

In the final step, either the acid for _R601 = t-Bu (Boc protection) or the hydrolysis for _R601 = Bn (CBz protection) is used to remove the carbamate protecting group of 603. Other amine protecting groups known in the art may be used. Amine 604 is then converted to product 605 using any of Schemes I, II, or II, or any other method that may be available.

Examples 53-60 can be synthesized using the following general synthetic procedure described in Scheme VIII. The synthesis begins with the amino alcohol 701 whose "L" moiety is the linking group. In some embodiments, 701 is 4-hydroxypiperidine.

The amino alcohol 701 is then reacted with the arene 702 to give the arylamine substitution product 703. In certain embodiments, the arene 702 is substituted with an electron _- removing group that facilitates a direct SNA reaction. In certain embodiments, the substitution reaction is assisted by the presence of a metal catalyst. Alcohol 703 is then converted to carbamate product 704 using either Scheme IV or V, or any other method that may be available.

Examples 61-70 can be synthesized using the following general synthetic procedures described in Scheme VIII. In the first step, sulfonyl chloride 801 is reacted with arylamine 103 as defined in Scheme I to give sulfonamide 802. The TBS group is removed by treatment with any acid of the fluoride ion in the second step to give 803.

Example 71 can be synthesized using the following general synthesis procedure described in Scheme IX. In the first step, the amine 901 is reacted with sulfuryl chloride to give the acid chloride 902. In the next step, the acid chloride 902 is reacted with the arylamine 103 as defined to give the sulfonamide 903. The TBS group is removed by treatment with any acid of the fluoride ion in the second step to give 904.

Examples 72-75 can be synthesized using the following general synthetic procedure described in Scheme X. In the first step, the arylamine 103 defined in Scheme I is converted to oxazolidinone 1001 when treated with 2-bromoethanol and chlorosulfonylisocyanate. In the next step, amine 1002 is reacted with 1001 to form the sulfonylurea 1003. In the final step, the TBS group is removed by treatment with any acid of the fluoride ion in the second step to give 1004.

Examples 77-87 can be synthesized using the following general synthetic procedure described in Scheme XI. In the first step, the carbamate-protected cyclic amine 1101 (n = 1, 2) is reacted with a suitable aryl halide to form the binding product 1102. In the next step, the carbamate protecting group can be removed to give the secondary amine 1103, which can then be treated in the Scheme I or Scheme II step to give 1104.

Example 88 can be synthesized using the following general synthetic procedure described in Scheme I. Aryl or heteroaryl alcohol 1201 is converted to chloroformate 1202 using (COCl ₂ ) ₃ in the presence of a base. As used herein and elsewhere, the formula HO-Ar-OTBS of 1201 represents an aryl compound substituted with both an OH group and an OTBS group. Formula 1201 comprises, for example, 4-[(tert-butyldimethylsilyl) oxy] phenol and 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-ol. Chloroformate is then reacted with amine 1203 in the presence of base to give carbamate 1204. In the final step, the TBS group is removed with either acid or fluoride to give 1205.

Example 89 can be synthesized using the following general synthetic procedure described in Scheme I. Carboxylic acid 1301 binds to arylamine 103 using a carbodiimide reagent such as EDCI (shown). In the second step, the TBS group is removed with either acid or fluoride to give 1303.

The present invention is further illustrated by the following examples.

Chromatography procedure Instrument "A": 2 # SHIMADZU.

Instrument "B": 2 # -Analytical HPLC-SHIMADZU.

Column "A": XBride OBD C18 preparative column, 30x150 mmx5 m.

Column "B": XBride OBD C18 preparative column, 19x250mmx5μm.

Column "C": XSelect CSH C18 OBD preparative column, 19x250 mm, 5 μm.

Column "D": Xselect CSH C18 OBD column 30x150mm 5μm.

Column "E": SunFire C18 OBD preparative column, 19 mm x 250 mm, 5 μm.

ＣＨ_２Ｃｌ_２（４０ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（３．７ｇ、１６．４９ｍｍｏｌ、１．００当量）、４－フルオロフェニルクロロギ酸塩（４．３ｇ、２４．６３ｍｍｏｌ、１．５０当量）、およびＥｔ_３Ｎ（５ｇ、４９．４１ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌し、次いで、３×８０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：１０）を使用してシリカゲルクロマトグラフィーで精製し、１．８ｇ（３０％）の表題化合物を白色固体として得た。 Intermediate Intermediate "A"
4-Fluorophenyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (3.7 g, 16.49 mmol, 1.00 eq) in CH ₂ Cl ₂ (40 mL), 4-fluorophenylchloroformate (4) A solution of .3 g, 24.63 mmol, 1.50 eq) and Et 3N (5 g _, 49.41 mmol, 3.00 eq) was stirred at room temperature for 2 hours and then extracted with 3 x 80 mL EtOAc. .. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1:10) to give 1.8 g (30%) of the title compound as a white solid.

LC-MS: (ES, m / z): 363
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 7.93 (dd, J = 3.0, 0.7 Hz, 1H), 7.69 (dd, J = 8. 9, 0.7Hz, 1H), 7.35 (dd, J = 9.0, 3.0Hz, 1H), 7.25 (d, J = 6.6Hz, 4H), 0.95 (s, 9H) ), 0.19 (s, 6H).

ステップ１．４－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］アニリンの合成

ＤＭＦ（５０ｍＬ）中の４－アミノフェノール（５ｇ、４５．８２ｍｍｏｌ）の溶液に、イミダゾール（６．２４ｇ）を少量ずつ加え、続いてＴＢＳＣｌ（８．２６ｇ）を０℃で５分間にわたって攪拌しながら滴下した。得られた溶液を室温で２時間攪拌し、次いで、１００ｍＬ Ｈ_２Ｏを加えてクエンチし、２×１５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：５）を使用してシリカゲルクロマトグラフィーで精製し、４ｇ（３９％）の表題化合物をオフホワイトの油として得た。 Intermediate "B"
4-Fluorophenyl N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] carbamate

Step 1.4-Synthesis of [(tert-butyldimethylsilyl) oxy] aniline

Add imidazole (6.24 g) in small portions to a solution of 4-aminophenol (5 g, 45.82 mmol) in DMF (50 mL), followed by TBSCl (8.26 g) at 0 ° C. for 5 minutes with stirring. Dropped. The resulting solution was stirred at room temperature for 2 hours, then quenched with 100 mL _H2O and extracted with 2 x 150 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 5) to give 4 g (39%) of the title compound as an off-white oil.

LC-MS: (ES, m / z): 224
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 6.57 to 6.48 (m, 2H), 6.49 to 6.40 (m, 2H), 4.60 (s, 2H), 0. 92 (s, 9H), 0.11 (s, 6H).

ＣＨ_２Ｃｌ_２（２０ｍＬ）中の前のステップ（２ｇ、８．９５ｍｍｏｌ）からの生成物の溶液に、Ｅｔ_３Ｎ（１．８ｇ、１７．７９ｍｍｏｌ）を少量ずつ加え、続いて、４－フルオロフェニルクロロギ酸（１．８７ｇ、１０．７１ｍｍｏｌ）を０℃で２分間にわたって攪拌しながら滴下した。得られた溶液を０℃で２時間攪拌し、次いで、６０ｍＬのＨ_２Ｏを加えてクエンチし、２×１００ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：５）を使用してシリカゲルクロマトグラフィーで精製し、１．５ｇ（４６％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 Synthesis of 4-fluorophenyl N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] carbamate

To a solution of the product from the previous step (2 g, 8.95 mmol) in CH ₂ Cl ₂ (20 mL), add Et ₃ N (1.8 g, 17.79 mmol) in small portions, followed by 4-fluoro. Phenylchloroformic acid (1.87 g, 10.71 mmol) was added dropwise at 0 ° C. for 2 minutes with stirring. The resulting solution was stirred at 0 ° C. for 2 hours, then quenched with 60 mL of _H2O and extracted with 2 x 100 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 5) to give 1.5 g (46%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 362
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 6.5 Hz, 4H) , 6.88 to 6.77 (m, 2H), 0.94 (s, 9H), 0.17 (s, 6H).

ステップ１：４－フェニルピペリジン－１－カルボニルクロリドの合成

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の４－フェニルピペリジン（１ｇ、６．２０ｍｍｏｌ、１．００当量）、Ｅｔ_３Ｎ（１．３ｇ、１２．８５ｍｍｏｌ、２．００当量）、およびトリホスゲン（１．９ｇ、１．００当量）の溶液を、室温で６時間攪拌し、次いで、３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、８００ｍｇ（５８％）の表題化合物を固体として得た。 Scheme I
Example 1
N- (5-Hydroxypyridin-2-yl) -4-phenylpiperidine-1-carboxamide

Step 1: Synthesis of 4-phenylpiperidine-1-carbonyl chloride

₄ -Phenylpiperidine (1 g, 6.20 mmol, 1.00 eq), Et 3N (1.3 g, 12.85 mmol, 2.00 eq), and triphosgene (1.9 g) in CH ₂ Cl ₂ (10 mL). , 1.00 eq) was stirred at room temperature for 6 hours and then extracted with 30 mL of EtOAc. The mixed organic layer was concentrated under vacuum to give 800 mg (58%) of the title compound as a solid.

ピリジン（５ｍＬ）中の前のステップからの生成物（５００ｍｇ、２．２４ｍｍｏｌ、１．００当量）および５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（５０２ｍｇ、２．２４ｍｍｏｌ、１．００当量）の溶液を、３０℃で１６時間攪拌し、次いで、２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、分取ＴＬＣ（ＥｔＯＡｃ／ヘキサン１：２）で精製し、２００ｍｇ（２２％）の表題化合物を固体として得た。 LC-MS: (ES, m / z): 224
Step 2: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4-phenylpiperidine-1-carboxamide

Products from the previous step in pyridine (5 mL) (500 mg, 2.24 mmol, 1.00 eq) and 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (502 mg, 2.24 mmol,). The solution (1.00 eq) was stirred at 30 ° C. for 16 hours and then extracted with 20 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by preparative TLC (EtOAc / Hexanes 1: 2) to give 200 mg (22%) of the title compound as a solid.

ＨＣｌ水溶液（１．５ｍＬ）およびＴＨＦ（３ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４９ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。ＰＨを、Ｅｔ_３Ｎで７に調整した。粗生成物を、機器「Ｂ」；カラム「Ａ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大４８．０％の１８．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４８ｍｇ（３３％）の表題化合物を固体として得た。 LC-MS: (ES, m / z): 412
Step 3: Synthesis of N- (5-hydroxypyridin-2-yl) -4-phenylpiperidine-1-carboxamide

A solution of the product (200 mg, 0.49 mmol, 1.00 eq) from the previous step in aqueous HCl (1.5 mL) and THF (3 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. bottom. The pH was adjusted to ₇ with Et 3N. Crude products, instrument "B"; column "A"; mobile phase, water (0.1% FA) and ACN (up to 48.0% 18.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 48 mg (33%) of the title compound as a solid.

LC-MS: (ES, m / z): 298
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7.59 ( d, J = 8.9Hz, 1H), 7.36 to 7.08 (m, 6H), 4.34 to 4.22 (m, 2H), 2.92 to 2.63 (m, 3H), 1.82 to 1.70 (m, 2H), 1.53 (qd, J = 12.5, 4.0 Hz, 2H).

ステップ２：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－フルオロフェニル）ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、４（４－フルオロフェニル）ピペリジン（３００ｍｇ、１．６７ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌し、次いで、３×１５ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空内で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、１５０ｍｇ（６３％）の表題化合物を白色固体として得た。 Scheme II
Example 2
N- [5- [hydroxy] Pyridine-2-yl] -4- (4-fluorophenyl) piperidine-1-carboxamide

Step 2: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-fluorophenyl) piperidine-1-carboxamide

Products from the previous step in CH ₂ Cl ₂ (5 mL) (200 mg, 0.55 mmol, 1.00 eq), 4 (4-fluorophenyl) piperidine (300 mg, 1.67 mmol, 3.00 eq), And Et 3N ₍ 170 mg, 1.68 mmol, 3.00 eq) solution was stirred at room temperature for 2 hours and then extracted with 3 x 15 mL EtOAc. The mixed organic layer was concentrated in vacuo and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 150 mg (63%) of the title compound as a white solid.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３５ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空下で濃縮し、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大７０．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５６．９ ｍｇ（５２％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 430
Step 3: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-fluorophenyl) piperidine-1-carboxamide

A solution of the product (150 mg, 0.35 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and instrumented "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 70.0% 20.0% ACN in 7 minutes). The detector was purified by preparative-HPLC under UV 254/220 nm conditions to give 56.9 mg (52%) of the title compound as a white solid.

LC-MS: (ES, m / z): 316
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.28 (dd, J = 8.5, 5.6Hz, 2H), 7.18 to 7.04 (m, 3H), 4.27 (d, J = 13.1Hz, 2H), 2.91 to 2.64 (m, 3H), 1.81 to 1.64 (m, 2H), 1.51 (qd, J = 12.6, 4.0Hz, 2H) ).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－フェニルピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、１－フェニルピペラジン（２７０ｍｇ、１．６６ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２００ｍｇ（８８％）の表題化合物を白色の固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４１３ Example 3
N- (5-Hydroxypyridin-2-yl) -4-phenylpiperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4-phenylpiperazine-1-carboxamide

Intermediate "A" in CH ₂ Cl ₂ (3 mL) (200 mg, 0.55 mmol, 1.00 eq), 1-Phenylpiperazine (270 mg, 1.66 mmol, 3.00 eq), and Et ₃ N (170 mg). , 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours and then extracted with 2 x 20 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 200 mg (88%) of the title compound as a white solid. LC-MS: (ES, m / z): 413

２Ｎ ＨＣｌ水溶液（１．５ｍＬ）およびＴＨＦ（３ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４８ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大７５．０％の５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５４．７ ｍｇ（３８％）の表題化合物を白色固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4-phenylpiperazine-1-carboxamide

A solution of the product (200 mg, 0.48 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1.5 mL) and THF (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. Crude product (200 mg), instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 75.0% 5.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 54.7 mg (38%) of the title compound as a white solid.

LC-MS: (ES, m / z): 299
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.49-9.39 (m, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7 .59 (d, J = 8.9Hz, 1H), 7.28 to 7.08 (m, 3H), 6.96 (d, J = 8.1Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 3.59 (t, J = 5.0Hz, 4H), 3.12 (t, J = 5.0Hz, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－クロロフェニル）ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５ｍｍｏｌ、１．００当量）、４－（４－クロロフェニル）ピペリジン（３３０ｍｇ、１．６９ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２２０ｍｇ（８９％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４６。 Example 4
4- (4-Chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-chlorophenyl) piperidine-1-carboxamide

Intermediate "A" (200 mg, 0.5 mmol, 1.00 eq), 4- (4-chlorophenyl) piperidine (330 mg, 1.69 mmol, 3.00 eq) in CH ₂ Cl ₂ (3 mL), and Et. A solution of ₃ N (170 mg, 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 220 mg (89%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 446.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２２０ｍｇ、０．４９ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２２０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大８０．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１０２．８ｍｇ（６３％）の表題化合物を白色固体として得た。 Step 2: Synthesis of 4- (4-chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-1-carboxamide

A solution of the product (220 mg, 0.49 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. .. Crude product (220 mg), instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 80.0% 25.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 102.8 mg (63%) of the title compound as a white solid.

LC-MS: (ES, m / z): 332
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.48-9.27 (m, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7 .59 (d, J = 8.9Hz, 1H), 7.39 to 7.22 (m, 4H), 7.13 (dd, J = 9.0, 3.0Hz, 1H), 4.27 ( d, J = 13.2Hz, 2H) 2.91 to 2.64 (m, 2H), 1.80 to 1.68 (m, 2H), 1.51 (qd, J = 12.7, 3, .9Hz, 2H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－フルオロフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、１－（４－フルオロフェニル）ピペラジン（３００ｍｇ、１．６６ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、３×２０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２１０ ｍｇ（８８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３１ Example 5
4- (4-Fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-fluorophenyl) piperazine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol, 1.00 eq), 1- (4-fluorophenyl) piperazine (300 mg, 1.66 mmol, 3.00 eq) in CH ₂ Cl ₂ (3 mL), and. A solution of Et 3N ₍ 170 mg, 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours. The resulting solution was extracted with 3 x 20 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to 210 mg (88%). ) Was obtained as an off-white solid. LC-MS: (ES, m / z): 431

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２１０ｍｇ、０．４９ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２１０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６５．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、６８．２ｍｇ（４４％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of 4- (4-fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (210 mg, 0.49 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. .. Crude product (210 mg), instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 65.0% 20.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 68.2 mg (44%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 328
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.91 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.19 to 6.92 (m, 5H), 3.58 (t, J = 4.9Hz, 4H), 3.06 (t, J = 5.0Hz, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－メトキシフェニル）ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、４－（４－メトキシフェニル）ピペリジン（３２０ｍｇ、１．６７ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、２×１５ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２５０ ｍｇ（１０３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４２ Example 6
N- (5-Hydroxypyridin-2-yl) -4- (4-Methoxyphenyl) piperidine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-methoxyphenyl) piperidine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol, 1.00 eq), 4- (4-methoxyphenyl) piperidine (320 mg, 1.67 mmol, 3.00 eq) in CH ₂ Cl ₂ (3 mL), and. A solution of Et 3N ₍ 170 mg, 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 x 15 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to 250 mg (103%). The title compound of was obtained as an off-white solid. LC-MS: (ES, m / z): 442

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２３０ｍｇ、０．５２ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空下で濃縮した。粗生成物（２４０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大５０．０％の２０．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、９２．８ｍｇ（５５％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- (4-methoxyphenyl) piperidine-1-carboxamide

A solution of the product (230 mg, 0.52 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. Crude product (240 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 50.0% 20.0% ACN in 7 minutes); detector. Purified by preparative-HPLC at uv254 / 220 nm to give 92.8 mg (55%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 328
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.76 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7.60 (d) , J = 8.9Hz, 1H), 7.13 (td, J = 6.8, 3.3Hz, 3H), 6.90 to 6.79 (m, 2H), 4.32 to 4.20 ( m, 2H), 3.71 (s, 3H), 2.82 (td, J = 12.9, 2.5Hz, 2H), 2.50 (q, J = 1.9Hz, 1H), 1. 79 to 1.67 (m, 2H), 1.49 (qd, J = 12.6, 3.9Hz, 2H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（３－クロロフェニル）ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、４－（３－クロロフェニル）ピペリジン（３３０ｍｇ、１．６９ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２４０ ｍｇ（９８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４６ Example 7
N- [5-Hydroxy] Pyridine-2-yl] -4- (3-Chlorophenyl) piperidine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3-chlorophenyl) piperidine-1-carboxamide

Intermediate "A" in CH ₂ Cl ₂ (3 mL) (200 mg, 0.55 mmol, 1.00 eq), 4- (3-chlorophenyl) piperidine (330 mg, 1.69 mmol, 3.00 eq), and Et. A solution of ₃ N (170 mg, 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 x 20 mL CH ₂ Cl ₂ , the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to 240 mg ( 98%) of the title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 446

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物２４０ｍｇ、０．５４ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２４０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６０．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１０７．２ｍｇ（６０％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3-chlorophenyl) piperidine-1-carboxamide

A solution of 240 mg, 0.54 mmol, 1.00 eq of product from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (240 mg), instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 25.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 107.2 mg (60%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 332
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.36-7.29 (m, 2H), 7.25 (dt, J = 7.5, 1.6Hz, 2H), 7.13 (dd, J = 8.9, 3.0Hz, 1H), 4.27 (d, J = 13.2Hz, 2H), 2.79 (ddd, J = 21.3, 12.5, 9.5Hz, 3H), 1 .82 to 1.69 (m, 2H), 1.53 (qd, J = 12.7, 4.0 Hz, 2H).

ステップ１：４－ベンジル－Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、４－ベンジルピペリジン（２９０ｍｇ、１．６５ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２４０ｍｇ（９８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４２６ Example 8
4-Benzyl-N- (5-hydroxypyridin-2-yl) piperidine-1-carboxamide

Step 1: Synthesis of 4-benzyl-N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-1-carboxamide

Intermediate "A" in CH ₂ Cl ₂ (3 mL) (200 mg, 0.55 mmol, 1.00 eq), 4-benzylpiperidine (290 mg, 1.65 mmol, 3.00 eq), and Et ₃ N (170 mg). , 1.68 mmol, 3.00 eq) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 x 20 mL CH ₂ Cl ₂ , the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to 240 mg (98). %) The title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 426

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２３０ｍｇ、０．５４ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２３０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６０．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、９６．７ｍｇ（５７％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of 4-benzyl-N- (5-hydroxypyridin-2-yl) piperidine-1-carboxamide

A solution of the product (230 mg, 0.54 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. .. Crude product (230 mg), instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 25.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 96.7 mg (57%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 312
^{1 1} H NMR (300 MHz, methanol-d ₄ ) δ 7.80 (dd, J = 3.0, 0.7 Hz, 1H), 7.50 (dd, J = 8.9, 0.8 Hz, 1H), 7.34 to 7.11 (m, 6H), 4.13 (dq, J = 13.7, 2.2Hz, 2H), 2.85 (td, J = 13.3, 2.6Hz, 2H) , 2.58 (d, J = 7.1Hz, 2H), 1.92 to 1.65 (m, 3H), 1.23 (qd, J = 12.6, 4.2Hz, 2H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（プロパン－２－イル）ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、４－（プロパン－２－イル）ピペリジン（２１０ｍｇ、１．６５ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、２×１５ ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、１９０ｍｇ（９１％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３７８ Example 9
N- (5-Hydroxypyridin-2-yl) -4- (Propane-2-yl) piperidine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (propane-2-yl) piperidine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol, 1.00 eq), 4- (propane-2-yl) piperidine (210 mg, 1.65 mmol, 3.00 eq) in CH ₂ Cl ₂ (5 mL), And Et 3N (170 mg, _3.00 eq) solution was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 × 15 mL CH ₂ Cl ₂ and the mixed organic layer was concentrated under vacuum to give 190 mg (91%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 378

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（１９０ｍｇ、０．５０ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空下で濃縮した。粗生成物を、機器「Ｂ」；カラム「Ｃ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大４５．０％の１７．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し
１０６ｍｇ（８０％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- (propane-2-yl) piperidine-1-carboxamide

A solution of the product (190 mg, 0.50 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. Crude products, instrument "B"; column "C"; mobile phase, water (0.1% FA) and ACN (up to 45.0% 17.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 106 mg (80%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 264
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.70 (s, 1H), 7.82 to 7.74 (m, 1H), 7.58 (d, J) = 8.9Hz, 1H), 7.13 (d, J = 8.9, 3.0Hz, 1H), 4.19 (d, J = 13.4, 3.5Hz, 2H), 2.67 ( td, J = 12.4, 2.3Hz, 2H), 1.68 to 1.56 (m, 2H), 1.43 (d, J = 13.2, 6.7Hz, 1H), 1.31 ~ 0.97 (m, 3H), 0.87 (d, J = 6.7Hz, 6H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（３ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、ピペリジン（１４０ｍｇ、１．６４ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（１７０ｍｇ、３．００当量）の溶液を、室温で２時間攪拌した。得られた溶液を、２×１０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、１７０ｍｇ（９２％）の表題化合物を白色固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３３６ Example 10
N- (5-Hydroxypyridin-2-yl) piperidine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol, 1.00 eq), piperidine (140 mg, 1.64 mmol, 3.00 eq), and Et ₃ N (170 mg, 3.0 eq) in CH ₂ Cl ₂ (3 mL). The solution (00 eq) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 × 10 mL CH ₂ Cl ₂ and the mixed organic layer was concentrated under vacuum to give 170 mg (92%) of the title compound as a white solid. LC-MS: (ES, m / z): 336

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（１７０ｍｇ、０．５１ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物を、機器「Ｂ」；カラム「Ｅ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大５０．０％の５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７１ｍｇ（６３％）の表題化合物を緑色固体として得た。 Step 3: Synthesis of N- (5-hydroxypyridin-2-yl) piperidine-1-carboxamide

A solution of the product (170 mg, 0.51 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. .. Crude product, instrument "B"; column "E"; mobile phase, water (0.1% FA) and ACN (up to 50.0% 5.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 71 mg (63%) of the title compound as a green solid.

LC-MS: (ES, m / z): 222
^{1 1} H-NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.67 (s, 1H), 7.77 (d, J = 2.9Hz, 1H), 7.57 ( d, J = 8.9Hz, 1H), 7.12 (d, J = 8.9, 3.0Hz, 1H), 3.45 to 3.37 (m, 4H), 1.51 (m, 6H) ).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］アゼパン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ、１．００当量）、アゼパン（１６０ｍｇ、１．６１ｍｍｏｌ、３．００当量）、およびＥｔ_３Ｎ（３．００当量、１７０ｍｇ）の溶液を、室温で２時間攪拌した。得られた溶液を、２×１５ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、１８０ｍｇ（９３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３５０ Example 11
N- (5-Hydroxypyridin-2-yl) azepan-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] azepan-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol, 1.00 eq), azepane (160 mg, 1.61 mmol, 3.00 eq), and Et ₃ N (3.00 eq) in CH ₂ Cl ₂ (5 mL). , 170 mg) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 × 15 mL CH ₂ Cl ₂ and the mixed organic layer was concentrated under vacuum to give 180 mg (93%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 350

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．５１ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、ＥｔＯＡｃで抽出した。混合有機層を、機器「Ｂ」；カラム「Ｃ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大３１．０％の１２．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、６６．２ｍｇ（５５％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) azepan-1-carboxamide

A solution of the product (180 mg, 0.51 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours and then extracted with EtOAc. The mixed organic layer is fractionated under the conditions of instrument "B"; column "C"; mobile phase, water (0.1% FA) and ACN (up to 31.0% 12.0% ACN in 7 minutes). -Purified by HPLC to give 66.2 mg (55%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 236
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H) 10.23 (s, 1H), 7.94 to 7.76 (m, 3H), 3.55 (t, J) = 6.1Hz, 4H), 1.71 (d, J = 9.4, 4.7Hz, 4H), 1.53 (t, J = 4.9Hz, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（２－フルオロフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－（２－フルオロフェニル）－ピペラジン（２９８ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ）の溶液を、室温で１６時間攪拌した。得られた溶液を、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２３０ｍｇ（９７％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３１ Example 12
4- (2-Fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (2-fluorophenyl) piperazine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol) in CH ₂ Cl ₂ (5 mL), 1- (2-fluorophenyl) -piperazine (298 mg, 1.65 mmol), and Et ₃ N (170 mg, 1.68 mmol). ) Was stirred at room temperature for 16 hours. The resulting solution was extracted with 2 x 20 mL CH ₂ Cl ₂ , the mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to 230 mg ( 97%) of the title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 431

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２３０ｍｇ、０．５３ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２３０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大７５．０％の５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１０６．７ｍｇ（６３％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of 4- (2-fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (230 mg, 0.53 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. .. Crude product (230 mg), instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 75.0% 5.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 106.7 mg (63%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 317
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.18 to 7.00 (m, 5H), 3.70 to 3.52 (m, 4H), 3.05 to 2.93 (m, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（２，４－ジフルオロフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｇ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－（２，４－ジフルオロフェニル－ピペラジン（３２８ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣ Ｈ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：１）を使用してシリカゲルカラムクロマトグラフィーで精製し、２４０ｍｇ（９７％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４９。 Example 13
4- (2,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (2,4-difluorophenyl) piperazine-1-carboxamide

A solution of intermediate "A" (200 mg, 0.55 mmol), 1- (2,4-difluorophenyl _- piperazine (328 mg, 1.65 mmol), and Et 3N (170 mg) in CH ₂ Cl ₂ (5 g). Was stirred at room temperature for 16 hours and then extracted with 2 × 30 mL CH ₂ Cl _2. The mixed organic layer was concentrated under vacuum and silica gel column chromatography using EtOAc / hexane (1: 1). Purified with, 240 mg (97%) of the title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 449.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２４０ｍｇ、０．５４ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２４０ｍｇ）を、
機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大４５．０％の５．０％ＡＣＮ）の条件下で、分取－ＨＰＬＣで精製し、８９．７ｍｇ（５０％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of 4- (2,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (240 mg, 0.54 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (240 mg),
Instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and purification by preparative-HPLC under the conditions of ACN (up to 45.0% 5.0% ACN in 7 minutes). Then, 89.7 mg (50%) of the title compound was obtained as an off-white solid.

LC-MS: (ES, m / z): 335
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.28 to 6.92 (m, 4H), 3.64 to 3.54 (m, 4H), 2.93 (t, J = 4.9Hz, 4H) ..

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［４－（トリフルオロメチル）フェニル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－［４－（トリフルオロメチル）－フェニル］ピペラジン（３８１ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２６０ｍｇ（９８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８１ Example 14
N- (5-Hydroxypyridin-2-yl) -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol) in CH ₂ Cl ₂ (5 mL), 1- [4- (trifluoromethyl) -phenyl] piperazine (381 mg, 1.65 mmol), and Et ₃ N (170 mg). , 1.68 mmol) was stirred at room temperature for 16 hours and then extracted with 2 × 20 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 260 mg (98%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 481

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２６０ｍｇ、０．５４ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２６０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大８５．０％の７．０％ＡＣＮ）の条件を使用して、分取－ＨＰＬＣで精製し、１０２．９ｍｇ（５２％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

A solution of the product (260 mg, 0.54 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (260 mg) was subjected to the conditions of instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 85.0% 7.0% ACN in 7 minutes). It was used and purified by preparative-HPLC to give 102.9 mg (52%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 367
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.94 (s, 1H), 7.80 (d, J = 3.0Hz, 1H), 7.55 (dd) , J = 28.2, 8.7Hz, 3H), 7.25-6.94 (m, 3H), 3.60 (dd, J = 6.6, 3.7Hz, 4H), 3.30 ( dd, J = 6.5, 3.8Hz, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－メトキシフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－（４－メトキシフェニル）ピペラジン（３１８ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２３０ｍｇ（９４％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４３。 Example 15
N- (5-Hydroxypyridin-2-yl) -4- (4-methoxyphenyl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-methoxyphenyl) piperazine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol) in CH ₂ Cl ₂ (5 mL), 1- (4-methoxyphenyl) piperazine (318 mg, 1.65 mmol), and Et ₃ N (170 mg, 1.68 mmol). The solution was stirred at room temperature for 16 hours and then extracted with 2 × 20 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 230 mg (94%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 443.

２Ｎ ＨＣｌ水溶液（４ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２３０ｍｇ、０．５２ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２３０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大７０．０％の５．０％ＡＣＮ）の条件を使用して、分取－ＨＰＬＣで精製し、８４．２ｍｇ（４９％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- (4-methoxyphenyl) piperazine-1-carboxamide

A solution of the product (230 mg, 0.52 mmol) from the previous step in 2N HCl aqueous solution (4 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (230 mg) was subjected to the conditions of instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 70.0% 5.0% ACN in 7 minutes). It was used and purified by preparative-HPLC to give 84.2 mg (49%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 329
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.89 (s, 1H), 7.79 (dd, J = 2.9, 0.7 Hz, 1H), 7 .59 (dd, J = 9.0, 0.7Hz, 1H), 7.13 (dd, J = 9.0, 2.9Hz, 1H), 6.99-6.88 (m, 2H), 6.88-6.78 (m, 2H), 3.68 (s, 3H), 3.58 (t, J = 5.0Hz, 4H), 2.98 (dd, J = 6.0, 3) .7Hz, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（ピリミジン－２－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、２－（ピペラジン－１－イル）ピリミジン（２７２ｍｇ、１．６６ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ、３．００当量）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２００ｍｇ（８７％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４１５。 Example 16
N- (5-Hydroxypyridin-2-yl) -4- (pyrimidine-2-yl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (pyrimidine-2-yl) piperazine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol) in CH ₂ Cl ₂ (5 mL), 2- (piperazine-1-yl) pyrimidine (272 mg, 1.66 mmol), and Et ₃ N (170 mg, 3.00). The solution (equivalent) was stirred at room temperature for 16 hours and then extracted with 2 × 30 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 200 mg (87%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 415.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４８ｍｍｏｌ）の溶液を、室温で２時間攪拌した。粗生成物（２００ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６０．０％の７．０％ＡＣＮ）の条件を使用して、分取－ＨＰＬＣで精製し、７７．２ｍｇ（５３％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- (pyrimidine-2-yl) piperazine-1-carboxamide

A solution of the product (200 mg, 0.48 mmol) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours. Crude product (200 mg) under the conditions of instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 7.0% ACN in 7 minutes). It was used and purified by preparative-HPLC to give 77.2 mg (53%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 415
^{1 1} H NMR (300 MHz, methanol-d ₄ ) 5 8.36 (d, J = 4.7 Hz, 2H), 7.83 (d, J = 3.0 Hz, 1H), 7.52 (d, J = 8.9Hz, 1H), 7.21 (dd, J = 8.9, 3.0Hz, 1H), 6.64 (t, J = 4.8Hz, 1H), 3.94 to 3.83 (m). 4H) 3.68 to 3.58 (m, 4H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（ピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－（ピリジン－２－イル）ピペラジン（２７０ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２２０ｍｇ（９６％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４１４。 Example 17
N- (5-Hydroxypyridin-2-yl) -4- (pyridin-2-yl) piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (pyridin-2-yl) piperazine-1-carboxamide

A solution of intermediate "A" (200 mg, 0.55 mmol), 1- (pyridin- ₂ -yl) piperazine (270 mg, 1.65 mmol), and Et 3N (170 mg) in CH ₂ Cl ₂ (5 mL). The mixture was stirred at room temperature for 16 hours and then extracted with 2 × 20 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 220 mg (96%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 414.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２２０ｍｇ、０．５３ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２２０ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６０．０％の７．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、９０．５ｍｇ（５７％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridine-2-yl) -4- (pyridin-2-yl) piperazine-1-carboxamide

A solution of the product (220 mg, 0.53 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (220 mg) under the conditions of instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 7.0% ACN in 7 minutes). Purification by preparative-HPLC gave 90.5 mg (57%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 300
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.89 (s, 1H), 8.12 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.64 to 7.48 (m, 2H), 7.13 (dd, J = 8.9, 3.0Hz, 1H), 6.85 (d, J = 8.6Hz, 1H), 6.70 to 6.60 (m, 1H), 3.52 (m, 8H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［５－（トリフルオロメチル）ピリジン－２－イル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペラジン（３８３ｍｇ、１．６６ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ、３．００当量）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２００ｍｇ（７５％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８２。 Example 18
N- (5-Hydroxypyridin-2-yl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

Intermediate "A" (200 mg, 0.55 mmol) in CH ₂ Cl ₂ (5 mL), 1- [5- (trifluoromethyl) pyridin-2-yl] piperazine (383 mg, 1.66 mmol), and Et ₃ A solution of N (170 mg, 3.00 eq) was stirred at room temperature for 16 hours and then extracted with 2 × 30 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 200 mg (75%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 482.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４２ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大５５．０％の２０．０％ＡＣＮ）の条件を使用して、分取－ＨＰＬＣで精製し、８０ｍｇ（５２％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

A solution of the product (200 mg, 0.42 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (200 mg) under the conditions of instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 55.0% 20.0% ACN in 7 minutes). It was used and purified by preparative-HPLC to give 80 mg (52%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 368
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.92 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.80 (dd) , J = 7.6, 2.7Hz, 2H), 7.60 (d, J = 8.9Hz, 1H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 6. 98 (d, J = 9.1 Hz, 1H), 3.71 to 3.51 (m, 8H).

ステップ１：Ｎ－ベンジル－４－フェニルシクロヘキサン－１－アミンの合成

ＣＨ_２Ｃｌ_２（１００ｇ）中の４－フェニルシクロヘキサン－１－オン（８．１ｇ、４６．４９ｍｍｏｌ、１．００当量）、ベンジルアミン（５ｇ、４６．６６ｍｍｏｌ、１．００当量）、およびＮａＢＨ（ＯＡｃ）_３（１９．８ｇ、９３．４２ｍｍｏｌ、２．００当量）の溶液を、室温で１ ６時間攪拌し、次いで、２×３００ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、４ｇ（３２％）の表題化合物をオフホワイト固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：２６６ Example 19
3- (5-Hydroxypyridin-2-yl) -1-[(1r, 4r) -4-phenylcyclohexyl] urea

Step 1: Synthesis of N-benzyl-4-phenylcyclohexane-1-amine

4-Phenylcyclohexane-1-one (8.1 g, 46.49 mmol, 1.00 eq), benzylamine (5 g, 46.66 mmol, 1.00 eq), and NaBH (8.1 g, 46.49 mmol, 1.00 eq) in CH ₂ Cl ₂ (100 g). A solution of OAc) ₃ (19.8 g, 93.42 mmol, 2.00 eq) was stirred at room temperature for 16 hours and then extracted with 2 x 300 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 4 g (32%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 266

ＭｅＯＨ（１０ｍｇ）中の前のステップからの生成物（５００ｍｇ、１．８８ｍｍｏｌ、１．００当量）、およびＡｃＯＨ（１ｍｇ）の溶液を、Ｐｄ／Ｃ（１００ｍｇ）上で、３０℃で１６時間攪拌した。固体を、濾過により除去し、濾液を真空下で濃縮して、３００ｍｇ（９１％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：１７６。 Step 2: Synthesis of 4-phenylcyclohexane-1-amine

A solution of the product (500 mg, 1.88 mmol, 1.00 eq) from the previous step in MeOH (10 mg) and AcOH (1 mg) on Pd / C (100 mg) at 30 ° C. for 16 hours. bottom. The solid was removed by filtration and the filtrate was concentrated under vacuum to give 300 mg (91%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 176.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（３００ｍｇ、１．７１ｍｍｏｌ）、中間体「Ａ」（１８６ｍｇ、０．５１ｍｍｏｌ）、およびＥｔ_３Ｎ（１７３ｍｇ、１．７１ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：１）を使用してシリカゲルクロマトグラフィーで精製し、２２０ｍｇ（３０％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４２６。 Step 3: Synthesis of 3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1-[(1r, 4r) -4-phenylcyclohexyl] urea

A solution of the product (300 mg, 1.71 mmol) from the previous step in CH ₂ Cl ₂ (5 mL), intermediate "A" (186 mg, 0.51 mmol), and Et 3N ₍ 173 mg, 1.71 mmol). Was stirred at room temperature for 16 hours and then extracted with 50 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 1) to give 220 mg (30%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 426.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２２０ｍｇ、０．５２ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２２０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３ 水溶液、およびＡＣＮ（７分間で最大６０．０％の２５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、４３．４ ｍｇ（２６％）の表題化合物をオフホワイトの固体として得た。 Step 4: Synthesis of 3- (5-hydroxypyridin-2-yl) -1-[(1r, 4r) -4-phenylcyclohexyl] urea

A solution of the product (220 mg, 0.52 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (220 mg) under the conditions of instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 25.0% ACN in 7 minutes). Purification by preparative-HPLC gave 43.4 mg (26%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 312
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.74 (s, 1H), 7.74 (t, J = 5.7Hz, 2H), 7.27 (p) , J = 7.2, 6.1Hz, 7H), 7.23 to 7.09 (m, 1H), 3.57 (br, 1H), 2.51 (s, 1H), 2.02 (m). , 2H), 1.83m, 2H), 1.56 (br q, J = 12.6Hz, 2H), 1.32 (br q, J = 12.8Hz, 2H).

ステップ１：３－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－（オキサン－４－イル）尿素の合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、オキサン－４－アミン（１６７ｍｇ、１．６５ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、１９０ｍｇ（９８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３５２。 Example 20
3- (5-Hydroxypyridin-2-yl) -1- (oxan-4-yl) urea

Step 1: Synthesis of 3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- (oxan-4-yl) urea

A solution of intermediate "A" (200 mg, 0.55 mmol), oxane- ₄ -amine (167 mg, 1.65 mmol) and Et 3N (170 mg) in CH ₂ Cl ₂ (5 mL) at room temperature for 16 hours. It was stirred and then extracted with 2 × 30 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 190 mg (98%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 352.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１９０ｍｇ、０．５４ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１９０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３ 水溶液、およびＡＣＮ（７分間で最大２５．０％の５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、５５ｍｇ（４３％）の表題化合物をオフホワイトの固体として得た。 Step 2.3 Synthesis of 3- (5-hydroxypyridin-2-yl) -1- (oxan-4-yl) urea

A solution of the product (190 mg, 0.54 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (190 mg) under the conditions of instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 25.0% 5.0% ACN in 7 minutes). Purification by preparative-HPLC gave 55 mg (43%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 238
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.75 (s, 1H), 7.85 (d, J = 7.3Hz, 1H), 7.72 (d) , J = 2.9Hz, 1H), 7.25 (d, J = 8.9Hz, 1H), 7.13 (dd, J = 8.9, 2.9Hz, 1H), 3.88-3. 78 (m, 2H), 3.78 to 3.68 (m, 1H), 3.46 to 3.31 (m, 2H), 1.87 to 1.73 (m, 2H), 1.38 ( m, 2H).

ステップ１．３－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－シクロヘキシル尿素の合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、シクロヘキサナミン（１６２ｍｇ、１．６３ｍｍｏｌ）、およびＥｔ_３Ｎ（１７０ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、１８０ｍｇ（９３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３５０。 Example 21
1-cyclohexyl-3- (5-hydroxypyridin-2-yl) urea

Step 1.3-Synthesis of 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1-cyclohexylurea

A solution of intermediate "A" (200 mg, 0.55 mmol), cyclohexanamine (162 mg, 1.63 mmol), and Et 3N ₍ 170 mg) in CH ₂ Cl ₂ (5 mL) was stirred at room temperature for 16 hours. Then, it was extracted with 2 × 30 mL of CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 180 mg (93%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 350.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．５１ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３ 水溶液、およびＡＣＮ（７分間で最大５２．０％の１０．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、５６ｍｇ（４６％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 3-cyclohexyl-3- (5-hydroxypyridin-2-yl) urea

A solution of the product (180 mg, 0.51 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (180 mg) under the conditions of instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 52.0% 10.0% ACN in 7 minutes). Purification by preparative-HPLC gave 56 mg (46%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 236
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.72 (s, 1H), 7.85-7.75 (m, 1H), 7.70 (d, J) = 2.9Hz, 1H), 7.23 (d, J = 8.9Hz, 1H), 7.12 (dd, J = 8.9, 2.9Hz, 1H), 3.52 (tp, J = 10.0, 3.7Hz, 1H), 1.86 to 1.73 (m, 2H), 1.65 (m, 2H), 1.52 (dd, J = 11.9, 5.8Hz, 1H) ), 1.25 (m, 5H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（５－クロロピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

０°ＣでのＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（１５０ｍｇ、０．４１ｍｍｏｌ、１．００当量）、および１－（５－クロロピリジン－２－イル）ピペラジン（８２ｍｇ、０．４１ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ、３．００当量）の溶液を、１６で攪拌しながら室温まで温め、次いで、真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１６０ｍｇ（８６％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４８。 Example 22
4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-chloropyridine-2-yl) piperazine-1-carboxamide

Intermediate "A" (150 mg, 0.41 mmol, 1.00 eq) in CH ₂ Cl ₂ (5 mL) at 0 ° C, and 1- (5-chloropyridine-2-yl) piperazine (82 mg, 0). A solution of .41 mmol _, 1.00 eq) and Et 3N (126 mg, 1.25 mmol, 3.00 eq) was warmed to room temperature with stirring at 16 and then concentrated under vacuum with EtOAc / Hexanes (126 mg, 1.25 mmol, 3.00 eq). Purification by silica gel chromatography using 1/2) gave 160 mg (86%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 448.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１６０ｍｇ、０．３６ｍｍｏｌ）の溶液に、室温で２Ｎ ＨＣｌ（１ｍＬ）を加えた。得られた溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１６０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３ 水溶液、およびＡＣＮ（７分間で最大３２．０％の３１．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、７４．３ｍｇ（６２％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 Synthesis of 4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

To a solution of the product (160 mg, 0.36 mmol) from the previous step in THF (2 mL) was added 2N HCl (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product (160 mg) under the conditions of instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 32.0% 31.0% ACN in 7 minutes). Purification by preparative-HPLC gave 74.3 mg (62%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 334
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.89 (s, 1H), 8.12 (d, J = 2.7Hz, 1H), 7.79 (d) , J = 2.9Hz, 1H), 7.68 to 7.53 (m, 2H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 6.90 (d, J = 9.1Hz, 1H), 3.63 to 3.46 (m, 8H).

ステップ１．Ｔｅｒｔ－ブチル４－（２，４－ジクロロフェニル）ピペラジン－１－カルボキシレートの合成

トルエン（２０ｍＬ）中のＴｅｒｔ－ブチルピペラジン－１－カルボキシレート（２ｇ、１７．５４ｍｍｏｌ）、１－ブロモ－３，５－ジクロロベンゼン（４ｇ、１７．７１ｍｏｌ）、ＮａＯｔＢｕ（２．５ｇ）、ＢＩＮＡＰ（１０８ｍｇ、０．１７ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）３（１６０ｍｇ、０．１７ｍｍｏｌ、０．０１当量）の溶液を、Ｎ_２下で１６時間、８０℃で攪拌し、次いで、５０ｍＬのＨ_２Ｏを加えてクエンチし、２ｘ６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、３．３ｍｇ（５７％）の表題化合物をオフホワイトの固体として得た。 Example 23
4- (2,4-dichlorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (2,4-dichlorophenyl) piperazine-1-carboxylate

Tert-butylpiperazin-1-carboxylate (2 g, 17.54 mmol) in toluene (20 mL), 1-bromo-3,5-dichlorobenzene (4 g, 17.71 mol), NaOtBu (2.5 g), BINAP ( A solution of 108 mg, 0.17 mmol), Pd ₂ (dba) 3 (160 mg, 0.17 mmol, 0.01 equivalent) was stirred under N ₂ for 16 hours at 80 ° C., followed by 50 mL of H ₂ O. In addition, it was quenched and extracted with 2x60 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 3.3 mg (57%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 331
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 8.7, 2.5 Hz, 1H), 7.17 ( d, J = 8.7Hz, 1H), 3.47 (t, J = 4.9Hz, 4H), 2.90 (t, J = 5.0Hz, 4H), 1.42 (s, 9H).

１，４－ジオキサン（６ｍＬ）中の前のステップからの生成物（１ｇ、３．０２ｍｍｏｌ）の溶液に、４Ｍ ＨＣｌ／ジオキサン（３ｍＬ）を加えた。得られた溶液を、室温で６時間攪拌し、次いで、真空内で濃縮し、２００ｍｇ（２９％）の表題化合物を淡黄色固体として得た。 Step 2.1-Synthesis of (2,4-dichlorophenyl) piperazine

4M HCl / dioxane (3 mL) was added to a solution of the product (1 g, 3.02 mmol) from the previous step in 1,4-dioxane (6 mL). The resulting solution was stirred at room temperature for 6 hours and then concentrated in vacuo to give 200 mg (29%) of the title compound as a pale yellow solid.

LC-MS: (ES, m / z): 231
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 7.13 ( d, J = 8.7Hz, 1H) 2.85 (Hept, J = 3.3Hz, 8H).

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．４０ｍｍｏｌ）、Ｅｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）、および１－（２，４－ジクロロフェニル）ピペラジン（１１４ｍｇ、０．４９ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えてクエンチし、２ｘ２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１８０ｍｇ（９３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８１。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (2,4-dichlorophenyl) piperazine-1-carboxamide

Products from the previous step in CH ₂ Cl ₂ (5 mL) (150 mg, 0.40 mmol), Et ₃ N (126 mg, 1.25 mmol), and 1- (2,4-dichlorophenyl) piperazine (114 mg, 0). The solution (.49 mmol) was stirred at room temperature for 16 hours, then quenched with 20 mL of _H2O and extracted with 2x20 mL of EtOAc. The mixed organic layer was purified by silica gel column chromatography using EtOAc / Hexanes (1/2) to give 180 mg (93%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 481.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３７ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大６４．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７３．０ｍｇ（５３％）の表題化合物をオフホワイトの固体として得た。 Step 4.4 Synthesis of 4- (2,4-dichlorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.37 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. Crude product (180 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 64.0% 35.0% ACN in 8 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 73.0 mg (53%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 367
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.89 (s, 1H), 7.80 (d, J = 3.0Hz, 1H), 7.71-7 .53 (m, 2H), 7.37 (dd, J = 8.6, 2.5Hz, 1H), 7.28-7.09 (m, 2H), 3.60 (m, 4H), 2 .95 (m, 4H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（５－フルオロピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（１５０ｍｇ、０．４１ｍｍｏｌ）、１－（５－フルオロピリジン－２－イル）ピペラジン（７５ｍｇ、０．４１ｍｍｏｌ）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１５０ｍｇ（８４％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３２ Example 24
4- (5-Fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-fluoropyridine-2-yl) piperazine-1-carboxamide

Intermediate "A" (150 mg, 0.41 mmol) in CH ₂ Cl ₂ (5 mL), 1- (5-fluoropyridin-2-yl) piperazine (75 mg, 0.41 mmol), and Et ₃ N (126 mg, 126 mg,). The 1.25 mmol) solution was stirred at room temperature for 16 hours and then extracted with 2 x 20 mL of EtOAc. The mixed organic layer was purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 150 mg (84%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 432

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３５ｍｍｏｌ）の溶液に、室温で２Ｎ ＨＣｌ水溶液（１ｍＬ）を加えた。得られた溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１５０ｍｇ）を、機器「Ａ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３ 水溶液、およびＡＣＮ（７分間で最大４５．０％の２３．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、５４．７ｍｇ（５０％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 Synthesis of 4- (5-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added to a solution of the product (150 mg, 0.35 mmol) from the previous step in THF (2 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product (150 mg) under the conditions of instrument "A"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 45.0% 23.0% ACN in 7 minutes). Purification by preparative-HPLC gave 54.7 mg (50%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 318
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (br, 1H), 8.90 (s, 1H), 8.11 (d, J = 3.1 Hz, 1H), 7.79 (d) , J = 2.9Hz, 1H), 7.69-7.46 (m, 2H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 6.92 (dd, J = 9.3, 3.5Hz, 1H), 3.51 (m, 8H).

ステップ１．Ｔｅｒｔ－ブチル４－（３，４－ジフルオロフェニル）ピペラジン－１－カルボキシレートの合成

室温でのトルエン（２０ｍＬ）中のＴｅｒｔ－ブチルピペラジン－１－カルボキシレート（２ｇ、１７．５４ｍｍｏｌ）、１，２－ジフルオロ－４－ヨードベンゼン（４．２ｇ、１７．５０ｍｍｏｌ）、ＮａＯｔＢｕ（２．５ｇ）、ＢＩＮＡＰ（１０８ｍｇ、０．１７ｍｍｏｌ、０．０１当量）、およびＰｄ_２（ｄｂａ）_３（１６０ｍｇ、０．１７ｍｍｏｌ）の溶液を、Ｎ_２下で１６時間、８０℃で攪拌した。次いで、反応を、４０ｍＬのＨ_２Ｏを加えてクエンチし、２ｘ５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、３．２ｍｇ（６１％）の表題化合物をオフホワイトの固体として得た。 Example 25
4- (3,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (3,4-difluorophenyl) piperazine-1-carboxylate

Tert-butylpiperazine-1-carboxylate (2 g, 17.54 mmol) in toluene (20 mL) at room temperature, 1,2-difluoro-4-iodobenzene (4.2 g, 17.50 mmol), NaOtBu (2. A solution of 5 g), BINAP (108 mg, 0.17 mmol, 0.01 equivalent), and Pd ₂ (dba) ₃ (160 mg, 0.17 mmol) was stirred under _N2 for 16 hours at 80 ° C. The reaction was then quenched by adding 40 mL of _H2O and extracted with 2x50 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 3.2 mg (61%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 299
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (dt, J = 10.6, 9.3 Hz, 1H), 7.00 (ddd, J = 14.2, 7.1, 3. 0Hz, 1H), 6.74 (dtd, J = 9.1, 3.3, 1.4Hz, 1H), 3.43 (t, J = 5.2Hz, 4H), 3.07 (dd, dd, J = 6.3, 4.2 Hz, 4H), 1.42 (s, 9H).

１，４－ジオキサン（６ｍＬ）中の前のステップからの生成物（１ｇ、３．３５ｍｍｏｌ）の溶液に、４Ｍ ＨＣｌ／ジオキサン（３ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で４時間攪拌した。ｐＨを、２Ｎ ＮａＨＣＯ_３で７に調整した。得られた溶液を、２×２０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、６４０ｍｇ（９６％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of (3,4-difluorophenyl) piperazine

4M HCl / dioxane (3 mL) was added dropwise to a solution of the product (1 g, 3.35 mmol) from the previous step in 1,4-dioxane (6 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH was adjusted to 7 with 2N NaHCO ₃ . The resulting solution was extracted with 2 x 20 mL EtOAc and the mixed organic layer was concentrated under vacuum to give 640 mg (96%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 199
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.22 (dt, J = 10.6, 9.3 Hz, 1H), 6.94 (ddd, J = 14.5, 7.1, 3. 0Hz, 1H), 6.69 (dtd, J = 8.5, 3.3, 1.5Hz, 1H), 3.06 to 2.93 (m, 4H), 2.87 to 2.72 ( m, 4H).

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．４１ｍｍｏｌ）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）の溶液に、１－（３，４－ジフルオロフェニル）ピペラジン（９８ｍｇ、０．４９ｍｍｏｌ）を室温で少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２ Ｏを加えることによりクエンチした。得られた溶液を、２×２０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１８０ｍｇ（９７％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４４９ Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3,4-difluorophenyl) piperazine-1-carboxamide

1- (3,4-difluorophenyl) piperazine in a solution of the product (150 mg, 0.41 mmol) from the previous step in CH ₂ Cl ₂ ( ₅ mL) and Et 3N (126 mg, 1.25 mmol). (98 mg, 0.49 mmol) was added in small portions at room temperature. The resulting solution was stirred at room temperature for 16 hours and then quenched by the addition of 20 mL of _H2O . The resulting solution was extracted with 2 x 20 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to 180 mg (97%). The title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 449

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．４０ｍｍｏｌ）の溶液に、室温で攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５７．０％の２５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、６８．７ｍｇ（５１％）の表題化合物をオフホワイトの固体として得た。 Step 4.4 Synthesis of 4- (3,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.40 mmol) from the previous step in THF (2 mL) with stirring at room temperature. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product (180 mg) under the conditions of instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 57.0% 25.0% ACN in 8 minutes). Purification by preparative-HPLC gave 68.7 mg (51%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 335
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.92 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.25 (q, J = 9.7Hz, 1H), 7.15 (d, J = 3.1Hz, 1H), 7.02 (ddd, J = 14. 2, 7.1, 3.0Hz, 1H), 6.76 (dd, J = 8.9, 4.1Hz, 1H), 3.58 (m, 4H), 3.12 (m, 4H).

ステップ１．Ｔｅｒｔ－ブチル４－（３，５－ジフルオロフェニル）ピペラジン－１－カルボキシレートの合成

トルエン（２０ｍＬ）中のＴｅｒｔ－ブチルピペラジン－１－カルボキシレート（２ｇ、１７．５４ｍｍｏｌ）、１，３－ジフルオロ－５－ヨードベンゼン（４．２ｇ、１７．５０ｍｍｏｌ）、ＮａＯｔＢｕ（２．５ｇ）、ＢＩＮＡＰ（１０８ｍｇ、０．１７ｍｍｏｌ）、およびＰｄ_２（ｄｂａ）_３（１６０ｍｇ、０．１７ｍｍｏｌ）の溶液を、１６時間、８０℃で攪拌し、次いで、４０ｍＬのＨ_２Ｏを加えることによりクエンチした。得られた溶液を、２×４０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、３．１ｇ（５９％）の表題化合物をオフホワイトの固体として得た。 Example 26
4- (3,5-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (3,5-difluorophenyl) piperazine-1-carboxylate

Tert-butylpiperazine-1-carboxylate (2 g, 17.54 mmol) in toluene (20 mL), 1,3-difluoro-5-iodobenzene (4.2 g, 17.50 mmol), NaOtBu (2.5 g), A solution of BINAP (108 mg, 0.17 mmol) and Pd ₂ (dba) ₃ (160 mg, 0.17 mmol) was stirred for 16 hours at 80 ° C. and then quenched by the addition of 40 mL of _H2O . The resulting solution was extracted with 2 x 40 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2), 3.1 g (59%). ) Was obtained as an off-white solid.

LC-MS: (ES, m / z): 299
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 6.69 to 6.57 (m, 2H), 6.49 (tt, J = 9.3, 2.2 Hz, 1H), 3.42 (t, J = 5.3Hz, 4H), 3.26 to 3.13 (m, 4H), 1.42 (s, 9H).

１，４－ジオキサン（６ｍＬ）中の前のステップからの生成物（１ｇ、３．３５ｍｍｏｌ）の溶液に、４Ｍ ＨＣｌ／ジオキサン（３ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で４時間攪拌した。ｐＨ値を、２Ｍ ＮａＨＣＯ_３で７に調整した。得られた溶液を、２×４０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、７２０ｍｇ（１０８％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of (3,5-difluorophenyl) piperazine

4M HCl / dioxane (3 mL) was added dropwise to a solution of the product (1 g, 3.35 mmol) from the previous step in 1,4-dioxane (6 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH value was adjusted to 7 with 2M NaHCO ₃ . The resulting solution was extracted with 2 x 40 mL EtOAc and the mixed organic layer was concentrated under vacuum to give 720 mg (108%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 199
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 6.65 to 6.51 (m, 2H), 6.44 (tt, J = 9.2, 2.2 Hz, 1H), 3.13 to 3. 06 (m, 4H), 2.86 to 2.73 (m, 4H).

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．４１ｍｍｏｌ）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）の溶液に、１－（３，５－ジフルオロフェニル）ピペラジン（９８ｍｇ、０．４９ｍｍｏｌ）を室温で少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１８０ｍｇ（９７％）の表題化合物をオフホワイトの固体として得た。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3,5-difluorophenyl) piperazine-1-carboxamide

1- ( _3,5 -difluorophenyl) piperazine in a solution of the product (150 mg, 0.41 mmol) from the previous step in CH ₂ Cl ₂ (5 mL) and Et 3N (126 mg, 1.25 mmol). (98 mg, 0.49 mmol) was added in small portions at room temperature. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 180 mg (97%) of the title compound as an off-white solid.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．４０ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、
機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大５５．０％の２５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、６４ｍｇ（４８％）の表題化合物をオフホワイトの固体として得た。 Step 4.4 Synthesis of 4- (3,5-difluorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (180 mg, 0.40 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 1 hour and then concentrated under vacuum. Crude product (180 mg),
Instrument "A"; Column "A"; Mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 55.0% 25.0% ACN in 8 minutes) on preparative-HPLC. Purification gave 64 mg (48%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 335
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.93 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 6.80 to 6.56 (m, 2H), 6.49 (tt, J = 9.2, 2.2 Hz, 1H), 3.57 (m, 4H), 3.24 (m, 4H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（４－シアノフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（１００ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（８４ｍｇ、０．８３ｍｏｌ）の溶液に、４－（ピペラジン－１－イル）ベンゾニトリル（５２ｍｇ、０．２８ｍｏｌ）を室温で加えた。得られた溶液を、室温で１６時間攪拌し、次いで、Ｈ_２ Ｏを加えることによりクエンチし、２×ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１１５ｍｇ（９５％）の表題化合物をオフホワイトの固体として得た。 Example 27
4- (4-Cyanophenyl) -N- (5-hydroxypyridine-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-cyanophenyl) piperazine-1-carboxamide

4- (Piperazine-1-yl) benzonitrile (52 mg) in a solution of intermediate "A" (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL) and Et ₃ N (84 mg, 0.83 mol). , 0.28 mol) was added at room temperature. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of _H2O and extracted with 2 x mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 115 mg (95%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１１５ｍｇ、０．２６ｍｍｏｌ）の溶液に、室温で２Ｎ ＨＣｌ（１ｍＬ）を加えた。得られた溶液を、室温で１時間攪拌し、次いで、真空下で濃縮した。粗生成物（１１５ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４５．０％の２０．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、４１．２ｍｇ（４８％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 438
Step 2.4 Synthesis of 4- (4-cyanophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

To a solution of the product (115 mg, 0.26 mmol) from the previous step in THF (2 mL) was added 2N HCl (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product (115 mg) under the conditions of instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 45.0% 20.0% ACN in 8 minutes). Purification by preparative-HPLC gave 41.2 mg (48%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 324
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.91 (s, 1H), 7.79 (d, J = 3.0Hz, 1H), 7.59 (d) , J = 8.8Hz, 3H), 7.14 (dd, J = 9.0, 3.0Hz, 1H), 7.12 to 7.00 (m, 2H), 3.59 (m, 4H) 3.38 (m, 4H).

ステップ１．Ｎ－［４－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］フェニル］－４－（２，４－ジフルオロフェニルｊピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．４１ｍｍｏｌ）の溶液に、Ｅｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）を少量ずつ加え、続いて、１（２，４－ジフルオロフェニル）ピペラジン（８２ｍｇ、０．４１ｍｍｏｌ、１．００当量）を少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、１５ｍＬのＨ_２Ｏを加えることによりクエンチし、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１７０ｍｇ（９２％）の表題化合物をオフホワイトの固体として得た。 Example 28
4- (2,4-difluorophenyl) -N- (4-hydroxyphenyl) piperazine-1-carboxamide

Step 1. Synthesis of N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] -4- (2,4-difluorophenylj piperazine-1-carboxamide)

To a solution of the product (150 mg, 0.41 mmol) from the previous step in CH ₂ Cl ₂ (5 mL) little by little Et ₃ N (126 mg, 1.25 mmol), followed by 1 (2,4). -Difluorophenyl) piperazine (82 mg, 0.41 mmol, 1.00 eq) was added in small portions. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 15 mL _H2O and extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 170 mg (92%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１７０ｍｇ、０．３８ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌し、次いで、真空下で濃縮した。粗生成物（１７０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（７分間で最大５８．０％の２０．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、８０．１ｍｇ（６３％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 448
Step 2.4 Synthesis of 4- (2,4-difluorophenyl) -N- (4-hydroxyphenyl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (170 mg, 0.38 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The crude product (170 mg) of the instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 58.0% 20.0% ACN in 7 minutes). Conditions were purified by preparative-HPLC to give 80.1 mg (63%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 334
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.31 (s, 1H), 7.29 to 6.93 (m, 5H), 6.67 to 6.58 (M, 2H), 3.54 (m, 4H), 2.93 (m, 4H).

ステップ１．Ｎ－［４－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］フェニル］－４－（４－フルオロフェニル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ｂ」（１５０ｍｇ、０．４１ｍｍｏｌ）の溶液に、Ｅｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）を少量ずつ加え、続いて、１－（４－フルオロフェニル）ピペラジン（７５ｍｇ、０．４２ｍｍｏｌ）を少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１７０ｍｇ（９５％）の表題化合物をオフホワイトの固体として得た。 Example 29
4- (4-Fluorophenyl) -N- (4-hydroxyphenyl) piperazine-1-carboxamide

Step 1. Synthesis of N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] -4- (4-fluorophenyl) piperazine-1-carboxamide

To a solution of intermediate "B" (150 mg, 0.41 mmol) in CH ₂ Cl ₂ (5 mL), Et 3N (126 mg, 1.25 mmol) was added in small portions, followed by 1- ( ₄ -fluorophenyl). ) Piperazine (75 mg, 0.42 mmol) was added in small portions. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 170 mg (95%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１７０ｍｇ、０．４０ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌し、次いで、真空下で濃縮した。粗生成物（１７０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大５８．０％の２０．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、７６．２ｍｇ（６１％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 430
Step 2.4 Synthesis of 4- (4-fluorophenyl) -N- (4-hydroxyphenyl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (170 mg, 0.40 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The crude product (170 mg) of the instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 58.0% 20.0% ACN in 8 minutes). Conditions were purified by preparative-HPLC to give 76.2 mg (61%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 316
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.32 (s, 1H), 7.23 to 7.13 (m, 2H), 7.11 to 6.92 (M, 4H), 6.68 to 6.57 (m, 2H), 3.53 (m, 4H), 3.06 (m, 4H).

ステップ１．Ｎ－［４－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］フェニル］－４－［４－（トリフルオロメチル）フェニル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ｂ」（１５０ｍｇ、０．４１ｍｍｏｌ）の溶液に、Ｅｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）を少量ずつ加え、続いて、１－［４－（トリフルオロ－メチル）フェニル］ピペラジン（９６ｍｇ、０．４２ｍｍｏｌ）を少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１８０ｍｇ（９０％）の表題化合物をオフホワイトの固体として得た。
ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８０
ステップ２．Ｎ－（４－ヒドロキシフェニル）－４－［４－（トリフルオロメチル）フェニル］ピペラジン－１－カルボキサミドの合成

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３８ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（７分間で最大６２．０％の２８．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、９１．４ｍｇ（６７％）の表題化合物をオフホワイトの固体として得た。
ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３６６
^１Ｈ ＮＭＲ（３００ＭＨｚ、ＤＭＳＯ－ｄ_６）δ ９．０２（ｓ、１Ｈ）、８．３４（ｓ、１Ｈ）、７．５０（ｄ、Ｊ＝８．５Ｈｚ、２Ｈ）、７．２３～７．１２（ｍ、２Ｈ）、７．０８（ｄ、Ｊ＝８．６Ｈｚ、２Ｈ）、６．６８～６．５８（ｍ、２Ｈ）、３．５５（ｍ、４Ｈ）、３．３０（ｍ、４Ｈ）。 Example 30
N- (4-Hydroxyphenyl) -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

Step 1. Synthesis of N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

To a solution of intermediate "B" (150 mg, 0.41 mmol) in CH ₂ Cl ₂ ( ₅ mL), Et 3N (126 mg, 1.25 mmol) was added in small portions, followed by 1- [4- (tri). Fluoro-methyl) phenyl] piperazine (96 mg, 0.42 mmol) was added in small portions. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 180 mg (90%) of the title compound as an off-white solid.
LC-MS: (ES, m / z): 480
Step 2. Synthesis of N- (4-hydroxyphenyl) -4- [4- (trifluoromethyl) phenyl] piperazin-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.38 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The crude product (180 mg) of the instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 62.0% 28.0% ACN in 7 minutes). Conditions were purified by preparative-HPLC to give 91.4 mg (67%) of the title compound as an off-white solid.
LC-MS: (ES, m / z): 366
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.34 (s, 1H), 7.50 (d, J = 8.5Hz, 2H), 7.23-7 .12 (m, 2H), 7.08 (d, J = 8.6Hz, 2H), 6.68 to 6.58 (m, 2H), 3.55 (m, 4H), 3.30 (m) 4H).

ステップ１．Ｎ－［４－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］フェニル］－４－［５－（トリフルオロメチルピリジン－２－イル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の中間体「Ｂ」（１５０ｍｇ、０．４１ｍｍｏｌ）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）の溶液に、１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペラジン（９６ｍｇ、０．４２ｍｍｏｌ）を少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１８０ｍｇ（９０％）の表題化合物をオフホワイトの固体として得た。 Example 31
N- (4-Hydroxyphenyl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

Step 1. Synthesis of N- [4-[(tert-butyldimethylsilyl) oxy] phenyl] -4- [5- (trifluoromethylpyridine-2-yl] piperazine-1-carboxamide

1- [5- (trifluoromethyl) pyridine- ₂ in a solution of intermediate "B" (150 mg, 0.41 mmol) in CH ₂ Cl ₂ (10 mL) and Et 3N (126 mg, 1.25 mmol). -Il] Piperazine (96 mg, 0.42 mmol) was added in small portions. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 180 mg (90%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３７ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（７分間で最大５５．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８５．２ｍｇ（６２％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 481
Step 2. Synthesis of N- (4-hydroxyphenyl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.37 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. Crude product (180 mg), instrument "A"; column "D"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 55.0% 25.0% ACN in 7 minutes); Purification by preparative-HPLC under conditions of detector, UV254 / 220 nm gave 85.2 mg (62%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 367
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.45 to 8.38 (m, 1H), 8.33 (s, 1H), 7.80 (dd, J) = 9.2, 2.6Hz, 1H), 7.23 to 7.12 (m, 2H), 6.97 (d, J = 9.1Hz, 1H), 6.69 to 6.58 (m, 2H), 3.66 (m, 4H), 3.52 (m, 4H).

ステップ１．３－［５－［（ｔｅｒｔ－ブリルジメチルシリル）オキシ］ピリジン－２－イル］－１－（１－フェニルピペリジン－４－イル）尿素の合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（２００ｍｇ、０．５ｍｍｏｌ）、１－フェニルピペリジン－４－アミン（１００ｍｇ、０．５７ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（１６８ｍｇ、１．６６ｍｍｏｌ）の溶液を、室温で一晩攪拌し、次いで、Ｈ_２Ｏを加えることによりクエンチし、ＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１５０ｍｇ（６４％）の表題化合物を白色固体として得た。 Example 32
3- (5-Hydroxypyridin-2-yl) -1- (1-phenylpiperidine-4-yl) urea

Step 1.3- [5-[(tert-bryldimethylsilyl) oxy] pyridin-2-yl] -1- (1-phenylpiperidine-4-yl) urea synthesis

Intermediate "A" (200 mg, 0.5 mmol) in CH ₂ Cl ₂ (5 mL), 1-phenylpiperidine-4-amine (100 mg, 0.57 mmol, 1.00 eq), and Et ₃ N (168 mg, 168 mg,). The solution (1.66 mmol) was stirred overnight at room temperature, then quenched by the addition of _H2O and extracted with EtOAc. The mixed organic layer was concentrated under vacuum to give 150 mg (64%) of the title compound as a white solid.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３５ｍｍｏｌ）の溶液を、室温で４時間攪拌し、次いで、ＥｔＯＡｃで抽出した。混合有機層を濃縮し、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５２．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、ｍＬ生成物を得、４２．３ ｍｇ（３９％）の表題化合物を白色固体として得た。 LC-MS (ES, m / z): 427.5
Step 2.3 Synthesis of 3- (5-hydroxypyridin-2-yl) -1- (1-phenylpiperidine-4-yl) urea

A solution of the product (150 mg, 0.35 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 4 hours and then extracted with EtOAc. Concentrate the mixed organic layer, instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 52.0% 20.0% ACN in 8 minutes); detector, Purification by preparative-HPLC under UV 254/220 nm conditions gave the mL product to give 42.3 mg (39%) of the title compound as a white solid.

LC-MS: (ES, m / z): 313.2
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.78 (s, 1H), 7.91 (s, 1H), 7.71 (d, J = 3.0Hz) , 1H), 7.29-7.10 (m, 4H), 6.95 (d, J = 8.2Hz, 2H), 6.75 (t, J = 7.3Hz, 1H), 3.76 ~ 3.66 (m, 1H), 3.59 ~ 3.49 (m, 2H), 2.94 ~ 2.82 (m, 2H), 1.98 ~ 1.88 (m, 2H), 1 .57 to 1.43 (m, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［４－（トリフルオロメチル）ピリジン－２－イル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）、１－［４－（トリフルオロメチル）ピリジン－２－イル］ピペラジン（６４ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１１０ｍｇ（８３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８２ Example 33
N- (5-Hydroxypyridin-2-yl) -4- [4- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [4- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

4-Fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL), 1- [4- (trifluoromethyl) ) Pyridine- ₂ -yl] A solution of piperazine (64 mg, 0.28 mmol) and Et 3N (84 mg, 0.83 mmol) was stirred at room temperature for 16 hours and then quenched by the addition of 20 mL of _H2O . And extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 110 mg (83%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 482

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１１０ｍｇ、２２８．４１ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１１０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５６．０％の２５．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７４．２ｍｇの表題化合物をオフホワイトの固体として得た。 Step 2. Synthesis of N- (5-hydroxypyridin-2-yl) -4- [4- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (110 mg, 228.41 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (110 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 56.0% 25.0% ACN in 8 minutes); detector. Purified by preparative-HPLC at uv254 / 220 nm to give 74.2 mg of the title compound as an off-white solid.

LC-MS: (ES, m / z): 368
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.92 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.78 (d) , J = 2.9Hz, 1H), 7.58 (d, J = 8.9Hz, 1H), 7.18 to 7.07 (m, 2H), 6.88 (dd, J = 5.2, 1.3Hz, 1H) 3.66 to 3.49 (m, 8H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（５－シアノピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）、６－（ピペラジン－１－イル）ピリジン－３－カルボニトリル（５２ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１００ｍｇ（８３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３９ Example 34
4- (5-Cyanopyridine-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-cyanopyridine-2-yl) piperazine-1-carboxamide

4-Fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg, 0.28 mmol), 6- (piperazine-1-yl) in CH ₂ Cl ₂ (5 mL) A solution of pyridine- ₃ -carbonitrile (52 mg, 0.28 mmol) and Et 3N (84 mg, 0.83 mmol) was stirred at room temperature for 16 hours and then quenched by the addition of 20 mL of _H2O . Extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 100 mg (83%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 439

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．２３ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６０．０％の５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５２．８ｍｇ（７１％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 Synthesis of 4- (5-cyanopyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

2N HCl (1 mL) was added dropwise to a solution of the product (100 mg, 0.23 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (100 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 60.0% 5.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 52.8 mg (71%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 325
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.92 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 7.85 (dd) , J = 9.1, 2.4Hz, 1H), 7.77 (d, J = 2.9Hz, 1H), 7.58 (d, J = 8.9Hz, 1H), 7.12 (dd, J = 8.9, 3.0Hz, 1H), 6.94 (d, J = 9.1Hz, 1H), 3.68 (m, 4H), 3.54 (m, 4H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（６－フルオロピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）、Ｅｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）、および１－（６－フルオロピリジン－２－イル）ピペラジン（５８ｍｇ、０．３２ｍｍｏｌ）の溶液。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１１０ｍｇ（８０％）をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３２ Example 35
4- (6-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (6-fluoropyridine-2-yl) piperazine-1-carboxamide

4-Fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL), Et ₃ N (84 mg, 0.83 mmol) ), And a solution of 1- (6-fluoropyridin-2-yl) piperazine (58 mg, 0.32 mmol). The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 110 mg (80%) as an off-white solid. LC-MS: (ES, m / z): 432

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１１０ｍｇ、０．２５ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を加えた。反応物を、室温で２時間攪拌し、次いで、真空下で濃縮し、粗生成物（１１０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４４．０％の２５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、５４．６ｍｇ（６８％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 Synthesis of 4- (6-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added to a solution of the product (110 mg, 0.25 mmol) from the previous step in THF (2 mL) with stirring. The reaction was stirred at room temperature for 2 hours and then concentrated under vacuum and the crude product (110 mg) was loaded onto the instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN. Purification by preparative-HPLC under conditions (up to 44.0% 25.0% ACN in 8 minutes) gave 54.6 mg (68%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 318
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.91 (s, 1H), 7.78 (d, J = 2.9Hz, 1H), 7.66 (ddd) , J = 7.5, 8.3, 8.3Hz, 1H), 7.58 (d, J = 8.9Hz, 1H), 7.12 (dd, J = 8.9, 2.9Hz, 1H) ), 6.70 (dd, J = 8.3, 2.7 Hz, 1H), 6.27 (m, 1H), 3.51 (m, 8H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［６－（トリフルオロメチル）ピリジン－２－イル］ピペラジン－１－カルボキサミド

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）、１－［６－（トリフルオロメチル）ピリジン－２－イル］ピペラジン（６４ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１１０ｍｇ（８３％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８１。 Example 36
N- (5-Hydroxypyridin-2-yl) -4- [6- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

Step 1. N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [6- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

4-Fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL), 1- [6- (trifluoromethyl) ) Pyridine- ₂ -yl] A solution of piperazine (64 mg, 0.28 mmol) and Et 3N (84 mg, 0.83 mmol) was stirred at room temperature for 16 hours and then quenched by the addition of 20 mL of _H2O . And extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 110 mg (83%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 481.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３１ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１５０ｍｇ）を、機器「Ａ」；カラム、ＳｕｎＦｉｒｅ Ｃ１８ ＯＢＤ分取カラム、１００＆＃６５５３３；、５μｍ、１９ｍｍＸ２５０ｍｍ；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大６６．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４６．５ｍｇ（４１％）の表題化合物をオフホワイトの固体として得た。 Step 2. Synthesis of N- (5-hydroxypyridin-2-yl) -4- [6- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (150 mg, 0.31 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (150 mg), instrument "A"; column, SunFire C18 OBD preparative column, 100 � 5 μm, 19 mmX250 mm; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 66 in 8 minutes). 0.0% 35.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 46.5 mg (41%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 368
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.92 (s, 1H), 7.82-7.68 (m, 2H), 7.59 (d, J) = 8.9Hz, 1H), 7.13 (m, 2H), 7.04 (d, J = 7.5Hz, 1H), 3.56 (m, 8H).

ステップ１．４－ベンジル－Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（１００ｍｇ、０．２８ｍｍｏｌ）の溶液に、Ｅｔ_３Ｎ（３当量）（８４ｍｇ）を攪拌しながら滴下し、続いて、１－ベンジルピペラジン（４９ｍｇ、０．２８ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、９４ｍｇ（８０％）の表題化合物を淡黄色の油として得た。 Example 37
4-Benzyl-N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1.4-Synthesis of 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperazine-1-carboxamide

Et 3N ( ₃ equivalents) (84 mg) was added dropwise to a solution of intermediate "A" (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL) with stirring, followed by 1-benzylpiperazine (1-benzylpiperazine). 49 mg, 0.28 mmol) was added. The resulting solution was stirred at room temperature for 16 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 94 mg (80%) of the title compound as a pale yellow oil.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（９４ｍｇ、０．２２ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（９４ｍｇ）を、機器「Ａ」；カラム「Ｂ」；移動相、水（０．０５％ＮＨ_３Ｈ_２Ｏ）、およびＡＣＮ（７分間で最大３５．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２８．９ｍｇ（４２％）の褐色固体を得た。 LC-MS (ES, m / z): 427.1
Step 2.4 Synthesis of 4-benzyl-N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (94 mg, 0.22 mmol) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (94 mg), instrument "A"; column "B"; mobile phase, water (0.05% NH _{3H 2} O), and ACN (up to 35.0% 20.0% in 7 minutes). ACN); Detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 28.9 mg (42%) brown solid.

LC-MS (ES, m / z): 313.0
^{1 1} H NMR (300 MHz, methanol-d ₄ ) δ 8.25 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H) , 7.44 to 7.27 (m, 5H), 7.20 (dd, J = 8.9, 2.8Hz, 1H), 3.78 (s, 2H), 3.60 (m, 4H) 2.71 (m, 4H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［（４－フルオロフェニル）メチル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の中間体「Ａ」（１００ｍｇ、０．２８ｍｍｏｌ）、１－［（４－フルオロフェニル）メチル］－ピペラジン（５４ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（３当量）（８４ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１００ ｍｇ（８２％）の表題化合物を淡黄色の油として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：４４５．１ Example 38
4-[(4-Fluorophenyl) methyl] -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4-[(4-fluorophenyl) methyl] piperazine-1-carboxamide

Intermediate "A" (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 mL), 1-[(4-fluorophenyl) methyl] -piperazine (54 mg, 0.28 mmol), and Et ₃ N (3 eq). ) (84 mg) was stirred at room temperature for 16 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 100 mg (82%) of the title compound as a pale yellow oil. LC-MS (ES, m / z): 445.1

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．２２ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム、Ｓｕｎｆｉｒｅ分取Ｃ１８ ＯＢＤカラム、１０ｕｍ、１９＊２５０ｍｍ；移動相、水（０．１％ＦＡ）およびＡＣＮ（１０分間で最大８．０％の２．０％ＡＣＮ）；検出器、ＵＶ、ＭＡＳＳ２２０／２５４ｎｍの条件で、分取－ＨＰＬＣで精製し、４９．９ｍｇ（６７％）の表題化合物を淡黄色油として得た。 Step 2.4 [Synthesis of (4-fluorophenyl) methyl] -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (100 mg, 0.22 mmol) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (100 mg), instrument "A"; column, Sunfire preparative C18 OBD column, 10 um, 19 * 250 mm; mobile phase, water (0.1% FA) and ACN (up to 8.0% in 10 minutes). 2.0% ACN); purified by preparative-HPLC under conditions of detector, UV, MASS 220/254 nm to give 49.9 mg (67%) of the title compound as a pale yellow oil.

LC-MS (ES, m / z): 331.0
^{1 1} H NMR (300 MHz, methanol-d ₄ ) δ 8.20 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H) , 7.46 to 7.33 (m, 2H), 7.20 (dd, J = 8.9, 2.9Hz, 1H), 7.10 (t, J = 8.7Hz, 2H), 3. 75 (s, 2H), 3.60 (m, 4H), 2.69 (m, 4H).

この化合物は、他に開示される方法を使用して調製することができる。 Example 39
1-[((5-Hydroxypyridin-2-yl) amino) carbonyl] -4- (pyridin-3-yl) piperazine

This compound can be prepared using the methods disclosed elsewhere.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］カルバメート（２００ｍｇ、０．５５ｍｍｏｌ）、Ｅｔ_３Ｎ（１７０ｍｇ、１．６８ｍｍｏｌ）、および１－（ピリジン－３－イル）ピペラジン（２７０ｍｇ、１．６５ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１４０ｍｇ（６１％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４１４。 Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (pyridin-3-yl) piperazine-1-carboxamide

4-Fluorophenyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate (200 mg, 0.55 mmol), Et ₃ N (170 mg, 1) in CH ₂ Cl ₂ (5 mL). A solution of .68 mmol) and 1- (pyridin-3-yl) piperazine (270 mg, 1.65 mmol) was stirred at room temperature for 16 hours and then extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 140 mg (61%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 414.

１Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１４０ｍｇ、０．３４ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１４０ｍｇ）を、機器「Ａ」；カラム「Ｂ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（７分間で最大４０．０％の５．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４９．７ｍｇ（４９％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of ((5-hydroxypyridin-2-yl) amino) carbonyl] -4- (pyridin-3-yl) piperazine

A solution of 1N HCl aqueous solution (1 mL) and the product (140 mg, 0.34 mmol) from the previous step in THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (140 mg), instrument "A"; column "B"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 40.0% 5.0% ACN in 7 minutes); Purification by preparative-HPLC under conditions of detector, uv254 / 220 nm gave 49.7 mg (49%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 300.
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.75-9.17 (m, 1H), 8.94 (s, 1H), 8.32 (d, J = 2.9Hz, 1H), 8 .01 (dd, J = 4.6, 1.3Hz, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d, J = 8.9Hz, 1H), 7. 42-7.31 (m, 1H), 7.22 (dd, J = 8.5, 4.5Hz, 1H), 7.13 (dd, J = 8.9, 3.0Hz, 1H), 3 .84-3.46 (m, 4H), 3.19m, 4H).

ステップ１：１－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－３－ヘキシル尿素の合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ、１．００当量）、１－イソシアネートヘキサン（１２７ｍｇ、１．００ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（３０３．６ｍｇ、３．００ｍｍｏｌ、３．００当量）の溶液を、室温で１８時間攪拌した。得られた溶液を、２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、分取ＴＬＣ（１：２）で精製し、３５０ｍｇ（１００％）の表題化合物を固体として得た。 Example 40
1-Hexyl-3- (5-hydroxypyridin-2-yl) urea

Step 1: Synthesis of 1- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -3-hexyl urea

5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (224 mg, 1.00 mmol, 1.00 eq), 1-isocyanate hexane (127 mg, 1.00 mmol) in CH ₂ Cl ₂ (5 mL), A solution of 1.00 eq) and Et 3N ₍ 303.6 mg, 3.00 mmol, 3.00 eq) was stirred at room temperature for 18 hours. The resulting solution was extracted with 20 mL CH ₂ Cl ₂ and the mixed organic layer was concentrated under vacuum and purified by preparative TLC (1: 2) to give 350 mg (100%) of the title compound as a solid. rice field.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（３５０ ｍｇ、１．００ ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空下で濃縮した。ＰＨを、Ｅｔ_３Ｎで７に調整した。粗生成物を、機器「Ｂ」；カラム「Ａ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大５０．０％の１０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１４０ｍｇ（５９％）の表題化合物を固体として得た。 LC-MS: (ES, m / z): 352
Step 2: Synthesis of 3-hexyl-1- (5-hydroxypyridin-2-yl) urea

A solution of the product (350 mg, 1.00 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The pH was adjusted to ₇ with Et 3N. Crude products, instrument "B"; column "A"; mobile phase, water (0.1% FA) and ACN (up to 50.0% 10.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under conditions of 220 nm gave 140 mg (59%) of the title compound as a solid.

LC-MS: (ES, m / z): 238
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 8.79 (s, 1H), 7.88 (s, 1H), 7.72 (d, 7 = 2.9 Hz) , 1H), 7.22 (d, J = 8.9Hz, 1H), 7.14 (dd, J = 8.9, 2.9Hz, 1H), 3.13 (q, J = 6.5Hz, 2H), 1.53 to 1.38 (m, 2H), 1.29 (dt, J = 9.4, 3.5Hz, 6H), 0.94 to 0.79 (m, 3H).

ステップ１：ヘキシルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］カルバメートの合成

ピリジン（５ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（３３６ｍｇ、１．５０ｍｍｏｌ）、およびヘキシルクロロギ酸（４９２ｍｇ、２．９９ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、５００ｍｇ（９５％）の表題化合物を白色固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３５３。 Example 41
Hexyl N- (5-hydroxypyridin-2-yl) carbamate

Step 1: Synthesis of hexyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (336 mg, 1.50 mmol) in pyridine (5 mL) and hexylchloroformic acid (492 mg, 2.99 mmol) at room temperature for 2 hours. It was stirred and then extracted with 2 x 30 mL of EtOAc. The mixed organic layer was purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 500 mg (95%) of the title compound as a white solid. LC-MS: (ES, m / z): 353.

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（５００ｍｇ、１．４２ｍｍｏｌ、１．００当量）、およびＢｕ_４ＮＦ（２４１ｍｇ、０．９２ｍｍｏｌ、２．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物を、機器「Ｂ」；カラム「Ｅ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大９０．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１８０ｍｇ（５３％）の表題化合物をオフホワイトの固体として得た。 Step 2: Synthesis of hexyl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (500 mg, 1.42 mmol, 1.00 eq) from the previous step in THF (5 mL) and Bu ₄ NF (241 mg, 0.92 mmol, 2.00 eq) at room temperature for 2 hours. It was stirred and then concentrated under vacuum. Crude product, instrument "B"; column "E"; mobile phase, water (0.1% FA) and ACN (up to 90.0% 25.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 180 mg (53%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 239
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 9.53 (s, 1H), 7.82 (d, J = 2.9Hz, 1H), 7.62 (d) , J = 8.9Hz, 1H), 7.19 (d, J = 8.9, 3.0Hz, 1H), 4.06 (t, J = 6.6Hz, 2H), 1.59 (q, J = 6.8Hz, 2H), 1.44 to 1.20 (m, 6H), 0.96 to 0.82 (m, 3H).

ステップ１：シクロヘキシルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］カルバメートの合成

ピリジン（３ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２ｍｇ、０．１０ｍｍｏｌ、１．００当量）、およびシクロヘキシルクロロギ酸（４８６ｍｇ、２．９９ｍｍｏｌ、３．００当量）の溶液を、室温で２時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空内で濃縮し、ＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用してシリカゲルカラムクロマトグラフィーで精製し、３００ｍｇ（８７３％）の表題化合物を白色固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３５１。 Example 42
Cyclohexyl N- (5-hydroxypyridin-2-yl) carbamate

Step 1: Synthesis of cyclohexyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (22 mg, 0.10 mmol, 1.00 eq) in pyridine (3 mL), and cyclohexylchloroformic acid (486 mg, 2.99 mmol, 3.00). Equivalent solution) was stirred at room temperature for 2 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated in vacuo and purified by silica gel column chromatography using CH ₂ Cl ₂ / MeOH (20: 1) to give 300 mg (873%) of the title compound as a white solid. LC-MS: (ES, m / z): 351.

ＴＨＦ（３ｍＬ）中の前のステップからの生成物（３００ｍｇ、０．８６ｍｍｏｌ、１．００当量）、およびＢｕ_４ＮＦ（４４７ｍｇ、２．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。残留物を、まずＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用したシリカゲルクロマトグラフィーで精製し、次いで、機器「Ａ」；カラム「Ｅ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大７４．０％の３３．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１２５．２ｍｇ（６２％）の表題化合物を白色固体として得た。 Step 2: Synthesis of cyclohexyl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (300 mg, 0.86 mmol, 1.00 eq) from the previous step in THF (3 mL) and Bu ₄ NF (447 mg, 2.00 eq) was stirred at room temperature for 2 hours and then , Concentrated under vacuum. The residue is first purified by silica gel chromatography using CH ₂ Cl ₂ / MeOH (20: 1), then instrument "A"; column "E"; mobile phase, water (0.1% FA) and ACN (up to 74.0% 33.0% ACN in 7 minutes); detector, purified by preparative-HPLC under UV254 / 220 nm conditions and 125.2 mg (62%) of the title compound as a white solid. Obtained.

LC-MS: (ES, m / z): 237
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 9.60 (s, 1H), 7.81 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.21 (d, J = 8.9, 3.0Hz, 1H), 4.62 (m, 1H), 1.78 (m, 4H), 1.58 ~ 1.13 (m, 6H).

ステップ１：４－フェニルシクロヘキサン－１－オールの合成

ＴＨＦ（８ｍＬ）中の４－フェニルシクロヘキサン－１－オン（５００ｍｇ、２．８７ｍｍｏｌ、１．００当量）、およびＬｉＡｌＨ_４（２２０ｍｇ、５．８０ｍｍｏｌ、２．００当量）の混合物を、室温で１６時間攪拌した。得られた固体を濾過により除去し、濾液を真空下で濃縮し、５００ｍｇ（９９％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：１５９。 Scheme V
Example 43
(1r, 4r) -4-Phenylcyclohexyl N- (5-hydroxypyridin-2-yl) carbamate

Step 1: Synthesis of 4-phenylcyclohexane-1-ol

A mixture of 4-phenylcyclohexane-1-one (500 mg, 2.87 mmol, 1.00 eq) in THF (8 mL) and LiAlH ₄ (220 mg, 5.80 mmol, 2.00 eq) at room temperature for 16 hours. Stirred. The resulting solid was removed by filtration and the filtrate was concentrated under vacuum to give 500 mg (99%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 159.

前のステップからの粗生成物（５００ｍｇ）を、機器「Ｂ」；カラム「Ｂ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大５１．０％の４５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１０８ ｍｇ（２２％）の表題化合物を白色固体として得た。 Step 2: Synthesis of (1r, 4r) -4-phenylcyclohexane-1-ol

The crude product (500 mg) from the previous step was added to the instrument "B"; column "B"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 51.0% in 7 minutes, 45.0%). ACN); Detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 108 mg (22%) of the title compound as a white solid.

ピリジン（１ｍＬ）およびＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（３００ｍｇ、１．７０ｍｍｏｌ、１．００当量）、トリホスゲン（２５６ｍｇ、０．８５ｍｍｏｌ、０．５０当量）、および５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（３８２ｍｇ、１．７０ｍｍｏｌ、１．００当量）の溶液を、室温で１６時間攪拌した。得られた溶液を、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、３００ｍｇ（４１％）の表題化合物をオフホワイトの固体として得た。 LC-MS-: (ES, m / z): 159
Step 3: Synthesis of (1r, 4r) -4-phenylcyclohexyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

Products from the previous step in pyridine (1 mL) and CH ₂ Cl ₂ (5 mL) (300 mg, 1.70 mmol, 1.00 eq), triphosgene (256 mg, 0.85 mmol, 0.50 eq), and 5 A solution of-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (382 mg, 1.70 mmol, 1.00 eq) was stirred at room temperature for 16 hours. The resulting solution was extracted with 2 x 30 mL CH ₂ Cl ₂ , the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to 300 mg (41). %) The title compound was obtained as an off-white solid.

ＴＨＦ（３ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４７ｍｍｏｌ、１．００当量）、およびＢｕ_４ＮＦ（２４５ｍｇ、０．９４ｍｍｏｌ、２．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ４ＨＣＯ３水溶液、およびＡＣＮ（７分間で最大６３．０％の３６．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、９１．１ｍｇ（６２％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 427
Step 4: Synthesis of (1r, 4r) -4-phenylcyclohexyl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (200 mg, 0.47 mmol, 1.00 eq) from the previous step in THF (3 mL) and Bu ₄ NF (245 mg, 0.94 mmol, 2.00 eq) at room temperature for 2 hours. It was stirred and then concentrated under vacuum. Crude product (200 mg), instrument "B"; column "A"; mobile phase, 10 mM NH4HCO3 aqueous solution, and ACN (up to 63.0% 36.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 91.1 mg (62%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 313
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.34 to 7.11 (m) , 6H), 4.67 (m, 1H), 2.56 (dt, J = 11.6, 3.6Hz, 1H), 2.08 (dd, J = 9.8, 5.1Hz, 2H) 1.84 (d, J = 11.5Hz, 2H) 1.70 to 1.36 (m, 4H).

ステップ１：１－フェニルピペリジン－４－イルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］カルバメートの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中のトリホスゲン（３００ｍｇ）の溶液に、１－フェニルピペリジン－４－オール（３５２ｍｇ、１．９９ｍｍｏｌ）を、３時間かけて加え、続いて、ピリジン（１ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（４４８ｍｇ、２．００ｍｍｏｌ、１．００当量）の溶液を、１６時間かけて加えた。得られた溶液を、室温でさらに１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空内で濃縮し、ＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用してシリカゲルクロマトグラフィーで精製し、２７０ｍｇ（３２％）の表題化合物をオフホワイトの固体として得た。 Example 44
1-Phenylpiperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1: Synthesis of 1-Phenylpiperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

To a solution of triphosgene (300 mg) in CH ₂ Cl ₂ (5 mL) was added 1-phenylpiperidine-4-ol (352 mg, 1.99 mmol) over 3 hours, followed by 5 in pyridine (1 mL). A solution of-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (448 mg, 2.00 mmol, 1.00 equivalent) was added over 16 hours. The resulting solution was stirred at room temperature for an additional 16 hours and then extracted with 2 × 30 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated in vacuo and purified by silica gel chromatography using CH ₂ Cl ₂ / MeOH (20: 1) to give 270 mg (32%) of the title compound as an off-white solid.

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（２７０ｍｇ、０．６３ｍｍｏｌ、１．００当量）、およびＢｕ_４ＮＦ（３３０ｍｇ、１．２６ｍｍｏｌ、２．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２７０ｍｇ）を、機器「Ｂ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大３７．０％の５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、６７．９ｍｇ（３４％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 428
Step 2: Synthesis of 1-Phenylpiperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (270 mg, 0.63 mmol, 1.00 eq) from the previous step in THF (5 mL) and Bu ₄ NF (330 mg, 1.26 mmol, 2.00 eq) at room temperature for 2 hours. It was stirred and then concentrated under vacuum. Crude product (270 mg) under the conditions of instrument "B"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 37.0% 5.0% ACN in 7 minutes). Purification by preparative-HPLC gave 67.9 mg (34%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 314
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.55 (s, 1H), 7.80 (d, J = 2.9Hz, 1H), 7.60 (d) , J = 8.9Hz, 1H), 7.27 to 7.12 (m, 3H), 7.01 to 6.89 (m, 2H), 6.75 (tt, J = 7.2, 1. 1Hz, 1H), 4.81 (m, 1H), 3.51 (m, 2H), 3.02 (m, 2H), 1.97m, 2H), 1.68 (m, 2H).

ステップ１．ｔｅｒｔ－ブチル４－（５－メトキシピリジン－２－イル）ピペラジン－１－カルボキシレートの合成

トルエン（２０ｍＬ）中のＴｅｒｔ－ブチルピペラジン－１－カルボキシレート（２ｇ、１０．７４ｍｍｏｌ）、２－ブロモ－５－メトキシピリジン（２ｇ、１０．６４ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（９８ｍｇ、０．１１ｍｍｏｌ）、ＢＩＮＡＰ（６７ｍｇ、０．１１ｍｍｏｌ）、およびＮａＯｔＢｕ（１．５ｇ、１５．６２ｍｍｏｌ）の溶液を、８０℃で１６時間攪拌し、次いで、Ｈ_２Ｏを加えることによりクエンチし、ＥｔＯＡｃで抽出した。混合有機層を真空内で濃縮し、ＥｔＯＡｃ／石油エーテル（１：３）を使用してシリカゲルクロマトグラフィーで精製し、２ｇ（６３％）の表題化合物を白色固体として得た。 Scheme VI
Example 45
N- (5-Hydroxypyridin-2-yl) -4- (5-methoxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (5-methoxypyridin-2-yl) piperazine-1-carboxylate

Tert-butylpiperazin-1-carboxylate (2 g, 10.74 mmol) in toluene (20 mL), 2-bromo-5-methoxypyridine (2 g, 10.64 mmol), Pd ₂ (dba) ₃ (98 mg, 0. A solution of 11 mmol), BINAP (67 mg, 0.11 mmol), and NaOtBu (1.5 g, 15.62 mmol) was stirred at 80 ° C. for 16 hours, then quenched by the addition of _H2O and extracted with EtOAc. bottom. The mixed organic layer was concentrated in vacuo and purified by silica gel chromatography using EtOAc / petroleum ether (1: 3) to give 2 g (63%) of the title compound as a white solid.

LC-MS: (ES, m / z): 294.3
^{1 1} HNMR (300 MHz, DMSO-d ₆ ) δ 7.87 (dd, 7 = 3.1, 0.6 Hz, 1H), 7.26 (dd, J = 9.1, 3.1 Hz, 1H), 6 .82 (dd, J = 9.2, 0.7Hz, 1H), 3.71 (s, 3H), 3.44 to 3.27 (m, 8H), 1.40 (s, 9H).

ジオキサン（５ｍ Ｌ）、４Ｎ ＨＣｌ／ジオキサン（３ｍＬ）中の前のステップからの生成物（１ｇ、３．４１ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。ｐＨを、ＮａＨＣＯ_３で８～９に調整した。得られた溶液を、ＥｔＯＡｃで抽出し、混合有機層を濃縮し、１ｇの表題化合物を黄色の油として得た。 Step 2.1-Synthesis of 5- (5-methoxypyridin-2-yl) piperazine

A solution of the product (1 g, 3.41 mmol) from the previous step in dioxane (5 mL), 4N HCl / dioxane (3 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The pH was adjusted to 8-9 with NaHCO ₃ . The resulting solution was extracted with EtOAc and the mixed organic layer was concentrated to give 1 g of the title compound as a yellow oil.

Ｃ Ｈ_２Ｃｌ_２（２０ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．５２ｍｍｏｌ）、中間体「Ａ」（２００ｍｇ、０．５５ｍｍｏｌ）、およびＥｔ３Ｎ（１６０ｍｇ）の溶液を、室温で１６時間攪拌し、次いで、真空下で濃縮し、ＥｔＯＡｃ／石油エーテル（１：３）を使用したシリカゲルクロマトグラフィーで精製し、１５０ｍｇ（６５％）の表題化合物を白色固体として得た。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-methoxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (100 mg, 0.52 mmol) from the previous step, intermediate "A" (200 mg, 0.55 mmol), and Et3N (160 mg) in CH ₂ Cl ₂ (20 mL) at room temperature 16 Stirred for hours, then concentrated under vacuum and purified by silica gel chromatography using EtOAc / petroleum ether (1: 3) to give 150 mg (65%) of the title compound as a white solid.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３４ｍｍｏｌ）の溶液を、室温で４時間攪拌し、次いで、真空下で濃縮した。粗生成物を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４６．０％の１０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２６．６ｍｇ（２４％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 444.5
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (5-methoxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (150 mg, 0.34 mmol) from the previous step in 2N HCl aqueous solution (2 mL) and THF (5 mL) was stirred at room temperature for 4 hours and then concentrated under vacuum. The crude product was instrumented as instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 46.0% 10.0% ACN in 8 minutes); detector, UV254 /. Purification by preparative-HPLC under 220 nm conditions gave 26.6 mg (24%) of the title compound as a white solid.

LC-MS: (ES, m / z): 330.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.88 (s, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.77 (d) , J = 2.9Hz, 1H), 7.57 (d, J = 8.9Hz, 1H), 7.26 (dd, J = 9.1, 3.1Hz, 1H), 7.12 (dd, J = 9.0, 3.0Hz, 1H), 6.85 (d, J = 9.1Hz, 1H), 3.71 (s, 3H), 3.53 (m, 4H), 3.40 ~ 3.31 (m, 4H).

ステップ１．Ｔｅｒｔ－ブチル４－［５－（トリフルオロメトキシ）ピリジン－２－イル］ピペラジン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の２－ブロモ－５－（トリフルオロメトキシ）ピリジン（５００ｍｇ、２．０７ｍｍｏｌ）、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（３８６ｍｇ、２．０７ｍｍｏｌ）、ＮａＯｔＢｕ（２９９ｍｇ）、ＢＩＮＡＰ（６５ｍｇ）、およびＰｄ_２（ｄｂａ）_３（９５ｍｇ、０．１０ｍｏｌ）の溶液を、８０℃で１６時間攪拌し、次いで、３０ｍＬのＨ_２Ｏを加えることによりクエンチした。得られた溶液を、２×６０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、２００ｍｇ（２８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３４８ Example 46
N- (5-Hydroxypyridin-2-yl) -4- [5- (trifluoromethoxy) pyridin-2-yl] piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- [5- (trifluoromethoxy) pyridin-2-yl] piperazine-1-carboxylate

2-bromo-5- (trifluoromethoxy) pyridine (500 mg, 2.07 mmol) in toluene (10 mL), tert-butylpiperazin-1-carboxylate (386 mg, 2.07 mmol), NaOtBu (299 mg), BINAP ( A solution of 65 mg) and Pd ₂ (dba) ₃ (95 mg, 0.10 mol) was stirred at 80 ° C. for 16 hours and then quenched by the addition of 30 mL of H ₂ O. The resulting solution was extracted with 2 x 60 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to 200 mg (28%). The title compound was obtained as an off-white solid. LC-MS: (ES, m / z): 348

ジオキサン（３ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．５８ｍｍｏｌ）の溶液に、攪拌しながらジオキサン（１ｍＬ）中の４Ｍ ＨＣｌ水溶液を滴下した。得られた溶液を、室温で４時間攪拌した。ｐＨを、２Ｎ ＮａＨＣＣＯ_３で７に調整した。得られた溶液を、５０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、１００ｍｇ（７０％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 5- [5- (trifluoromethoxy) Pyridine-2-yl] piperazine

A 4M HCl aqueous solution in dioxane (1 mL) was added dropwise to a solution of the product (200 mg, 0.58 mmol) from the previous step in dioxane (3 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH was adjusted to 7 with 2N NaHCCO ₃ . The resulting solution was extracted with 50 mL of EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 100 mg (70%) of the title compound. Was obtained as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（６８ｍｇ、０．２８ｍｍｏｌ）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）、およびＥｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１１６ｍｇ（８５％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 248
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [5- (trifluoromuethoxy) pyridin-2-yl] piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (68 mg, 0.28 mmol), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg) , 0.28 mmol), and Et 3N ₍ 84 mg, 0.83 mmol) were stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 50 mL EtOAc. .. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 116 mg (85%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１１６ｍｇ、０．３０ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１５０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５２．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、６４．６ｍｇ（４３％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 498
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- [5- (trifluoromethoxy) pyridin-2-yl] piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (116 mg, 0.30 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (150 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 52.0% 30.0% ACN in 8 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 64.6 mg (43%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 384
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.91 (s, 1H), 8.15 (m, 1H), 7.78 (m, 1H), 7. 65 to 7.53 (m, 2H), 7.12 (dd, J = 8.9, 3.0Hz, 1H), 6.95 (d, J = 9.3Hz, 1H), 3.53 (br) s, 8H).

ステップ１．Ｔｅｒｔ－ブチルＮ－［１－（４－フルオロフェニル）ピペリジン－３－イル］カルバメートの合成

エチレングリコール／イソプロパノール（１／１０ｍＬ）中の１－フルオロ－４－ヨードベンゼン（１ｇ、４．５０ｍｍｏｌ）、ＣｕＩ（８６ｍｇ、０．４５ｍｍｏｌ）、Ｋ_３ＰＯ_４（１．９ｇ、８．９５ｍｍｏｌ）、およびｔｅｒｔ－ブチルＮ－（ピペリジン－３－イル）カルバメート（９００ｍｇ、４．４９ｍｍｏｌ）の溶液を、９０℃で１ ６時間攪拌し、次いで、室温に冷却し、水（１００ｍＬ）で希釈した。得られた溶液を、３×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮し、ＥｔＯＡｃ／石油エーテル（１／４）を使用してシリカゲルクロマトグラフィーで精製し、５５０ｍｇ（４１％）の表題化合物を淡黄色の油として得た。 Example 47
1- [1- (4-Fluorophenyl) piperidine-3-yl] -3- (5-hydroxypyridin-2-yl) urea

Step 1. Synthesis of tert-butyl N- [1- (4-fluorophenyl) piperidine-3-yl] carbamate

1-Fluoro- _{4-iodobenzene (1 g, 4.50 mmol) in ethylene glycol / isopropanol (1/10 mL), CuI (86 mg, 0.45 mmol), K3 PO 4 (} 1.9 g, 8.95 mmol), And a solution of tert-butyl N- (piperidine-3-yl) carbamate (900 mg, 4.49 mmol) was stirred at 90 ° C. for 16 hours, then cooled to room temperature and diluted with water (100 mL). The resulting solution was extracted with 3 x 50 mL EtOAc. The mixed organic layer was washed with salt water, dried over Na ₂ SO ₄ , concentrated under vacuum and purified by silica gel chromatography using EtOAc / petroleum ether (1/4), entitled 550 mg (41%). The compound was obtained as a pale yellow oil.

ＣＦ_３ＣＯＯＨ／ＣＨ_２Ｃｌ_２（５／５ｍＬ）中の前のステップからの生成物（５５０ｍｇ、１．８７ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮し、９０ｍＬのＥｔＯＡｃに溶解し、飽和ＮａＨＣＯ_３水溶液で洗浄した。混合有機層を塩水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮し、２００ｍｇ（５５％）の表題化合物を淡黄色の油として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：１９５．１５ LC-MS (ES, m / z): 295.20
Step 2.1-Synthesis of (4-fluorophenyl) piperidine-3-amine

A solution of the product (550 mg, 1.87 mmol) from the previous step in CF ₃ COOH / CH ₂ Cl ₂ (5/5 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum to 90 mL. It was dissolved in EtOAc and washed with saturated aqueous NaHCO ₃ solution. The mixed organic layer was washed with brine, dried over anhydrous Na _{2 SO4} and concentrated under vacuum to give 200 mg (55%) of the title compound as a pale yellow oil. LC-MS (ES, m / z): 195.15

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップからの生成物（２００ｍｇ、１．０３ｍｍｏｌ）、Ｅｔ_３Ｎ（０．２９７ｍＬ）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（３７３ｍｇ、１．０３ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、３ｘ３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮し、ＥｔＯＡｃ／石油エーテル（１／４）を使用してシリカゲルクロマトグラフィーで精製し、２００ｍｇ（４４％）の表題化合物を淡黄色の油として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：４４５．３５ Step 3.3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [1- (4-fluorophenyl) piperidine-3-yl] urea synthesis

Product from previous step in CH ₂ Cl ₂ (10 mL) (200 mg, 1.03 mmol), Et ₃ N (0.297 mL), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy ] A solution of pyridine-2-ylcarbamate (373 mg, 1.03 mmol) was stirred at room temperature for 16 hours and then extracted with 3x30 mL of EtOAc. The mixed organic layer was dried on Na ₂ SO ₄ , concentrated under vacuum and purified by silica gel chromatography using EtOAc / petroleum ether (1/4) to give 200 mg (44%) of the title compound pale yellow. Obtained as oil. LC-MS (ES, m / z): 445.35

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（６ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４５ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物を、機器「Ａ」；カラム「Ａ」；移動相、水（０．０５％ＮＨ_３Ｈ_２Ｏ）、およびＡＣＮ（７分間で最大４０．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４５．７ ｍｇ（３１％）のオフホワイトの固体を得た。 Step 4.1-Synthesis of 1- [1- (4-fluorophenyl) piperidine-3-yl] -3- (5-hydroxypyridin-2-yl) urea

A solution of the product (200 mg, 0.45 mmol) from the previous step in 2N HCl aqueous solution (2 mL) and THF (6 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product was instrument "A"; column "A"; mobile phase, water (0.05% NH _{3H 2} O), and ACN (up to 40.0% 35.0% ACN in 7 minutes); Purification by preparative-HPLC under conditions of detector, UV254 / 220 nm to give 45.7 mg (31%) of off-white solid.

LC-MS (ES, m / z): 331.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 2.9 Hz) , 1H), 7.28 (d, J = 8.9Hz, 1H), 7.14 (dd, J = 8.9, 2.9Hz, 1H), 7.09 to 7.00 (m, 2H) , 7.00 to 6.91 (m, 2H), 3.90 to 3.73 (m, 1H), 3.40 (dd, J = 11.9, 3.5Hz, 1H), 3.21 ( d, J = 12.6Hz, 1H) 2.95 (t, J = 9.6Hz, 1H) 2.80 (dd, J = 11.7, 7.7Hz, 1H) 1.78 (s) , 2H) 1.70 to 1.56 (m, 1H), 1.48 (d, J = 8.6Hz, 1H).

ステップ１．Ｔｅｒｔ－ブチルＮ－［１－（４－クロロフェニル）ピペリジン－３－イル］カルバメートの合成

エチレングリコール／イソプロパノール（１／１０ｍＬ）中の１－クロロ－４－ヨードベンゼン（１ｇ、４．１９ｍｍｏｌ）、ＣｕＩ（８０ｍｇ、０．４２ｍｍｏｌ）、Ｋ_３ＰＯ_４（１．８ｇ、８．４８ｍｍｏｌ）、およびｔｅｒｔ－ブチルＮ－（ピペリジン－３－イル）カルバメート（８００ｍｇ、３．９９ｍｍｏｌ）の溶液を、９０℃で１ ６時間攪拌し、次いで、室温に冷却し、Ｈ_２Ｏ（１００ｍＬ）で希釈した。得られた混合物を、３×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮し、ＥｔＯＡｃ／石油エーテル（１／４）を使用してシリカゲルクロマトグラフィーで精製し、０．５ ｇ（３８％）の表題化合物を淡黄色の油として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：３１１．１５ Example 48
1- [1- (4-chlorophenyl) piperidine-3-yl] -3- (5-hydroxypyridin-2-yl) urea

Step 1. Synthesis of tert-butyl N- [1- (4-chlorophenyl) piperidine-3-yl] carbamate

1-Chloro- _{4-iodobenzene (1 g, 4.19 mmol) in ethylene glycol / isopropanol (1/10 mL), CuI (80 mg, 0.42 mmol), K3 PO 4 (} 1.8 g, 8.48 mmol), And a solution of tert-butyl N- (piperidine-3-yl) carbamate (800 mg, 3.99 mmol) was stirred at 90 ° C. for 16 hours, then cooled to room temperature and diluted with _H2O (100 mL). .. The resulting mixture was extracted with 3 x 50 mL EtOAc. The mixed organic layer was washed with salt water, dried over Na ₂ SO ₄ , concentrated under vacuum and purified by silica gel chromatography using EtOAc / petroleum ether (1/4) to 0.5 g (38%). ) Was obtained as a pale yellow oil. LC-MS (ES, m / z): 311.15

ＣＦ_３ＣＯＯＨ （５ｍＬ）／ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（５００ｍｇ、１．６１ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。残留物を３×３０ｍＬのＥｔＯＡｃに取り込み、ＮａＨＣＯ_３水溶液で洗浄した。混合有機層を真空下で濃縮し、２００ｍｇ（５９％）の表題化合物を淡黄色の油として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：２１１．１５ Step 2.1-Synthesis of (4-chlorophenyl) piperidine-3-amine

A solution of the product (500 mg, 1.61 mmol) from the previous step in CF ₃ COOH (5 mL) / CH ₂ Cl ₂ (5 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was incorporated into 3 x 30 mL EtOAc and washed with ₃ aqueous NaHCO solution. The mixed organic layer was concentrated under vacuum to give 200 mg (59%) of the title compound as a pale yellow oil. LC-MS (ES, m / z): 211.15

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．９５ｍｍｏｌ）、Ｅｔ_３Ｎ（０．２７５ｍＬ）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（３４５ｍｇ、０．９５ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、３ｘ３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮し、ＥｔＯＡｃ／石油エーテル（１／４）を使用して分取ＴＬＣで精製し、２００ｍｇ（４６％）の表題化合物を淡黄色の油として得た。 Step 3.3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [1- (4-chlorophenyl) piperidine-3-yl] urea synthesis

Product from previous step in CH ₂ Cl ₂ (10 mL) (200 mg, 0.95 mmol), Et ₃ N (0.275 mL), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy. A solution of pyridine-2-ylcarbamate (345 mg, 0.95 mmol) was stirred at room temperature for 16 hours and then extracted with 3x30 mL of EtOAc. The mixed organic layer was dried on Na ₂ SO ₄ , concentrated under vacuum and purified by preparative TLC using EtOAc / petroleum ether (1/4) to give 200 mg (46%) of the title compound pale yellow. Obtained as oil.

前のステップからの生成物（２００ｍｇ、０．４５ｍｍｏｌ）、２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（６ｍＬ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮し、機器「Ａ」；カラム「Ａ」；移動相、水（０．０５％ＮＨ_３Ｈ_２Ｏ）、およびＡＣＮ（７分間で最大４０．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、６５．３ ｍｇ（４３％）の表題化合物をオフホワイトの固体として得た。 Step 4.1-Synthesis of 1- [1- (4-chlorophenyl) piperidine-3-yl] -3- (5-hydroxypyridin-2-yl) urea

A solution of the product (200 mg, 0.45 mmol), 2N HCl aqueous solution (2 mL) and THF (6 mL) from the previous step was stirred at room temperature for 2 hours and then concentrated under vacuum to the instrument "A"; Column "A"; mobile phase, water (0.05% NH _{3H 2} O), and ACN (up to 40.0% 35.0% ACN in 7 minutes); detector, UV 254/220 nm conditions. Purification by preparative-HPLC gave 65.3 mg (43%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 347.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.84 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 2.9 Hz) , 1H), 7.40 to 7.08 (m, 4H), 7.04 to 6.87 (m, 2H), 3.78 (d, J = 9.4Hz, 1H), 3.50 (dd) , J = 11.9, 3.5Hz, 1H) 3.30 (s, 1H), 3.00 (t, J = 9.3Hz, 1H) 2.85 (dd, J = 12.1. 7.9Hz, 1H), 1.82 (d, J = 12.3Hz, 2H), 1.69 to 1.42 (m, 2H).

ステップ１．Ｔｅｒｔ－ブチルＮ－［１－（５－フルオロピリジン－２－イル）ピペリジン－４－イル］カルバメートの合成

トルエン（２０ｍＬ）中の２－ブロモ－５－フルオロピリジン（１ｇ、５．６８ｍｍｏｌ）、ＮａＯｔＢｕ（０．８ｇ）、ＢＩＮＡＰ（０．１３３ｇ）、ｔｅｒｔ－ブチルＮ－（ピペリジン－４－イル）カルバメート（１．１ｇ、５．４９ｍｍｏｌ）、およびＰｄ_２（ｄｂａ）_３（２６０ｍｇ、０．２８ｍｍｏｌ）の溶液を、８０°Ｃで１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、７００ｍｇ（４２％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：２９６。 Example 49
1- [1- (5-fluoropyridin-2-yl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

Step 1. Synthesis of tert-butyl N- [1- (5-fluoropyridin-2-yl) piperidine-4-yl] carbamate

2-Bromo-5-fluoropyridine (1 g, 5.68 mmol) in toluene (20 mL), NaOtBu (0.8 g), BINAP (0.133 g), tert-butyl N- (piperidine-4-yl) carbamate ( A solution of 1.1 g (5.49 mmol) and Pd ₂ (dba) ₃ (260 mg, 0.28 mmol) was stirred at 80 ° C. for 16 hours and then extracted with 2 × 30 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 700 mg (42%) of the title compound as an off-white solid. LC-MS (ES, m / z): 296.

ＣＨ_２Ｃｌ_２（６ｍＬ）中の前のステップからの生成物（７００ｍｇ、２．３７ｍｍｏｌ）の溶液に、攪拌しながらＣＦ_３ＣＯＯＨ（３ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌した。ｐＨを、ＮａＨＣＯ_３水溶液で８に調整した。得られた溶液を、３０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、３００ｍｇ（６５％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：１９６ Step 2.1-Synthesis of 5- (5-fluoropyridin-2-yl) piperidine-4-amine

CF ₃ COOH (3 mL) was added dropwise to a solution of the product (700 mg, 2.37 mmol) from the previous step in CH ₂ Cl ₂ (6 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH was adjusted to 8 with ₃ aqueous NaHCO. The resulting solution was extracted with 30 mL of EtOAc and the mixed organic layer was concentrated under vacuum to give 300 mg (65%) of the title compound as an off-white solid. LC-MS (ES, m / z): 196

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（５４ｍｇ、０．２８ｍｍｏｌ）の溶液に、Ｅｔ_３Ｎ（８４ｍｇ、０．８３ｍｍｏｌ）を少量ずつ加え、続いて、５－フルオロピリジン－２－イルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ）を少量ずつ加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１００ｍｇ（８１％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：４４６。 Step 3.3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [1- (5-fluoropyridine-2-yl) piperidine-4-yl] urea synthesis

To a solution of the product (54 mg, 0.28 mmol) from the previous step in CH ₂ Cl ₂ (5 mL) little by little Et 3N (84 mg, 0.83 mmol), followed by ₅ -fluoropyridine-. 2-Il N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (100 mg, 0.28 mmol) was added in small portions. The resulting solution was stirred at room temperature for 16 hours and then extracted with 2 × 30 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 100 mg (81%) of the title compound as an off-white solid. LC-MS (ES, m / z): 446.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．２２ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（０．０５％ＮＨ_３Ｈ_２Ｏ）、およびＡＣＮ（７分間で最大３５．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５１．８ｍｇ（７０％）の表題化合物を淡黄色の油として得た。 Step 4.1-Synthesis of 1- [1- (5-fluoropyridin-2-yl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (100 mg, 0.22 mmol) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (100 mg), instrument "A"; column "A"; mobile phase, water (0.05% NH _{3H 2} O), and ACN (up to 35.0% 20.0% in 7 minutes). ACN); detector, purified by preparative-HPLC under UV254 / 220 nm conditions to give 51.8 mg (70%) of the title compound as a pale yellow oil.

LC-MS (ES, m / z): 332
^{1 1} H NMR (300 MHz, methanol-d ₄ ) δ 8.00 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 9.0Hz, 1H), 7.22 (d) , J = 8.9Hz, 1H), 7.02 (d, J = 9.0Hz, 1H), 6.87 (dd, J = 9.6, 3.5Hz, 1H), 3.98 (m, 3H), 3.43 to 3.03 (m, 2H), 2.11 to 2.00 (m, 2H), 1.59 (m, 2H).

ステップ１．４－（６－フルオロピリジン－３－イル）ピペラジン－１－カルボキシレートの合成

トルエン中の５－ブロモ－２－フルオロピリジン（２００ｍｇ、１．１４ｍｍｏｌ）、ベンジルピペラジン－１－カルボキシレート（２５１ｍｇ、１．１４ｍｍｏｌ）、Ｃ_Ｓ２ＣＯ_３（１．１ｇ、３．３８ｍｍｏｌ）、ＢｒｅｔｔＰｈｏｓ（６ｍｇ）、およびＢｒｅｔｔＰｈｏｓ Ｐｄ Ｇ３触媒（１０ｍｇ）の溶液を、８０℃で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、９０ｍｇ（２５％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：３１５．９５ Example 50
4- (6-fluoropyridin-3-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1.4-Synthesis of piperazine-1-carboxylate of (6-fluoropyridin-3-yl) piperazine-1-carboxylate

5-bromo-2-fluoropyridine (200 mg, 1.14 mmol) in toluene, benzylpiperazine-1-carboxylate (251 mg, 1.14 mmol), _CS2 CO ₃ (1.1 g, 3.38 mmol), Brett Phos ( A solution of 6 mg) and a BenzylPhos Pd G3 catalyst (10 mg) was stirred at 80 ° C. for 16 hours and then extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 90 mg (25%) of the title compound as an off-white solid. LC-MS (ES, m / z): 315.95

ＭｅＯＨ（５ｍＬ）中の前のステップからの生成物（９０ｍｇ、０．２９ｍｍｏｌ）の溶液を、室温でＨ_２下およびＰｄ／Ｃ（１０ｍｇ）で１６時間攪拌した。固体を濾過により除去し、濾液を真空下で濃縮し、４０ｍｇ（７７％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：１８２．２ Step 2.1-Synthesis of (6-fluoropyridin-3-yl) piperazine

A solution of the product (90 mg, 0.29 mmol) from the previous step in MeOH ( ₅ mL) was stirred under H2 and Pd / C (10 mg) at room temperature for 16 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum to give 40 mg (77%) of the title compound as an off-white solid. LC-MS (ES, m / z): 182.2

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（４０ｍｇ、０．２２ｍｍｏｌ）、５－フルオロピリジン－２－イルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（８０ｍｇ、０．２２ｍｏｌ）、およびＥｔ_３Ｎ（６７ｍｇ、０．６６ ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、８０ｍｇ（８４％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：４３２．２。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (6-fluoropyridine-3-yl) piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (40 mg, 0.22 mmol), 5-fluoropyridin-2-yl N-5-[(tert-butyldimethylsilyl) oxy] pyridine-2- A solution of _ilcarbamate (80 mg, 0.22 mol) and Et 3N (67 mg, 0.66 mmol) was stirred at room temperature for 16 hours and then extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc EtOAc / Hexanes (1/2) to give 80 mg (84%) of the title compound as an off-white solid. LC-MS (ES, m / z): 432.2.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（８０ｍｇ、０．１９ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（８０ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大２８．０％の３．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２８．１ｍｇ（４８％）の表題化合物をオフホワイトの固体として得た。 Step 4.4 Synthesis of 4- (6-fluoropyridin-3-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (80 mg, 0.19 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (80 mg), instrument "A"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 28.0% 3.0% ACN in 7 minutes); detector Purified by preparative-HPLC under UV254 / 220 nm conditions to give 28.1 mg (48%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 318.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.93 (s, 1H), 7.84 (t, J = 2.5Hz, 1H), 7.78 (d) , J = 3.0Hz, 1H), 7.68 to 7.52 (m, 2H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 7.02 (dd, J = 8.9, 3.5Hz, 1H), 3.59 (m, 4H), 3.13m, 4H).

ステップ１．Ｔｅｒｔ－ブチルＮ－［１－（４－フルオロフェニル）ピペリジン－４－イル］カルバメートの合成

トルエン中の１－ブロモ－４－フルオロベンゼン（１ｇ、５．７１ｍｍｏｌ）、ｔｅｒｔ－ブチルＮ－（ピペリジン－４－イル）カルバメート（２．３ｇ、１１．４８ｍｍｏｌ）、ＮａＯｔＢｕ（１．６６ｇ、１．５ ０当量）、Ｒｕｐｈｏｓ（２６８ｍｇ）、およびＰｄ_２（ｄｂａ）_３（５２６ｍｇ、０．５７ｍｍｏｌ）の溶液を、Ｎ_２下で１６時間、８０℃で攪拌し、次いで、６０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、５９０ｍｇ（３５％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：２９５。 Example 51
1- [1- (4-fluorophenyl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

Step 1. Synthesis of tert-butyl N- [1- (4-fluorophenyl) piperidine-4-yl] carbamate

1-bromo-4-fluorobenzene (1 g, 5.71 mmol) in toluene, tert-butyl N- (piperidine-4-yl) carbamate (2.3 g, 11.48 mmol), NaOtBu (1.66 g, 1. A solution of 50 equivalents), Ruphos (268 mg), and Pd ₂ (dba) ₃ (526 mg, 0.57 mmol) is stirred under N ₂ for 16 hours at 80 ° C., then 60 mL of H ₂ O is added. It was quenched by this and extracted with 2 x 60 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 590 mg (35%) of the title compound as an off-white solid. LC-MS (ES, m / z): 295.

１，４－ジオキサン（１０ｍＬ）中の前のステップからの生成物（５９０ｍｇ、２．００ｍｍｏｌ）の溶液に、４Ｍ ＨＣｌ／ジオキサン（４ｍＬ）を室温で２分間にわたり攪拌しながら、滴下した。得られた溶液を、室温で４時間攪拌した。ｐＨを、２Ｎ ＮａＨＣＯ_３で７に調整した。得られた溶液を、２×５０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、１９０ｍｇ（４９％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 4- (4-fluorophenyl) piperidine-4-amine

4M HCl / dioxane (4 mL) was added dropwise to a solution of the product (590 mg, 2.00 mmol) from the previous step in 1,4-dioxane (10 mL) at room temperature for 2 minutes with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH was adjusted to 7 with 2N NaHCO ₃ . The resulting solution was extracted with 2 x 50 mL EtOAc and the mixed organic layer was concentrated under vacuum to give 190 mg (49%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 195
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.10 to 6.97 (m, 2H), 6.97 to 6.90 (m, 2H), 3.55 to 3.44 (m, 2H) 2.65 (td, J = 11.9, 2.7Hz, 3H), 1.76 (d, J = 12.7Hz, 2H), 1.39 to 1.22 (m, 2H).

前のステップからの生成物（１５０ｍｇ、０．４１ｍｍｏｌ）を含む４０ｍＬバイアルに、Ｅｔ_３Ｎ（１２６ｇ）を少量ずつ加え、続いて、ＣＨ_２Ｃｌ_２（５ｍＬ）中の１－（４－フルオロフェニル）ピペリジン－４－アミン（８０ｍｇ、０．４１ｍｍｏｌ）の溶液を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１８０ｍｇ（９８％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ（ＥＳ、ｍ／ｚ）：４４５ Step 3.3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [1- (4-fluorophenyl) piperidine-4-yl] urea synthesis

To a 40 mL vial containing the product (150 mg, 0.41 mmol) from the previous step, add Et ₃ N (126 g) in small portions, followed by 1- (4-fluorophenyl) in CH ₂ Cl ₂ (5 mL). ) A solution of piperidine-4-amine (80 mg, 0.41 mmol) was added. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 180 mg (98%) of the title compound as an off-white solid. LC-MS (ES, m / z): 445

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．４０ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５４．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５０．５ｍｇ（３８％）の表題化合物をオフホワイトの固体として得た。 Step 4.1-Synthesis of 1- [1- (4-fluorophenyl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.40 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (180 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 54.0% 25.0% ACN in 8 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 50.5 mg (38%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 331
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.76 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 2.8 Hz) , 1H), 7.24 (d, J = 8.8Hz, 1H), 7.12 (dd, J = 8.9, 2.9Hz, 1H), 7.08-6.88 (m, 4H) 3.67 (s, 1H), 3.42 (m, 2H), 2.82 (m, 2H), 1.91 (m, 2H), 1.58 to 1.44 (m, 2H).

ステップ１．Ｔｅｒｔ－ブチルＮ－［１－（４－クロロフェニル）ピペリジン－４－イル］カルバメートの合成

ＣＨ_２Ｃｌ_２（２０ｍＬ）中の（４－クロロフェニル）ボロン酸（１．５６ｇ、９．９８ｍｍｏｌ）、Ｃｕ（ＯＡｃ）_２（１．８１ｇ、９．９７ｍｍｏｌ）、ｔｅｒｔ－ブチルＮ－（ピペリジン－４－イル）カルバメート（１ｇ、４．９９ｍｍｏｌ）、およびＥｔ_３Ｎ（４．０４ｇ、３９．９２ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、５０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：５）を使用してシリカゲルクロマトグラフィーで精製し、２．５ｇ（１６１％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３１１。 Example 52
1- [1- (4-chlorophenyl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

Step 1. Synthesis of tert-butyl N- [1- (4-chlorophenyl) piperidine-4-yl] carbamate

CH ₂ Cl ₂ (20 mL) (4-chlorophenyl) boronic acid (1.56 g, 9.98 mmol), Cu (OAc) ₂ (1.81 g, 9.97 mmol), tert-butyl N- (piperidine-4) _-Il ) A solution of carbamate (1 g, 4.99 mmol) and Et 3N (4.04 g, 39.92 mmol) was stirred at room temperature for 16 hours and then quenched by the addition of 50 mL of _H2O . Extracted with 2 x 50 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 5) to give 2.5 g (161%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 311.

４Ｎ ＨＣｌ／ジオキサン（４ｍＬ）および１，４－ジオキサン（１０ｍＬ）中の前のステップからの生成物（１ｇ、３．２２ｍｍｏｌ）の溶液を、室温で４時間攪拌した。ｐＨを、２Ｎ ＮａＨＣＯ_３で７に調整した。得られた溶液を、２×５０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、２００ｍｇ（３０％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：２１１ Step 2.1-Synthesis of 4- (4-chlorophenyl) piperidine-4-amine

A solution of the product (1 g, 3.22 mmol) from the previous step in 4N HCl / dioxane (4 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 4 hours. The pH was adjusted to 7 with 2N NaHCO ₃ . The resulting solution was extracted with 2 x 50 mL EtOAc and the mixed organic layer was concentrated under vacuum to give 200 mg (30%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 211

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．４１ｍｍｏｌ）、１－（４－クロロフェニル）ピペリジン－４－アミン（８７ｍｇ、０．４１ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（１２６ｍｇ、１．２５ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、１８０ｍｇ（９５％）の表題化合物をオフホワイトの固体として得た。 Step 3: Synthesis of 3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [1- (4-chlorophenyl) piperidine-4-yl] urea

Products from the previous step in CH ₂ Cl ₂ (5 mL) (150 mg, 0.41 mmol), 1- (4-chlorophenyl) piperidine-4-amine (87 mg, 0.41 mmol, 1.00 eq), and. A solution of Et 3N ₍ 126 mg, 1.25 mmol) was stirred at room temperature for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 180 mg (95%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３９ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（１ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大５７．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８２．８ｍｇ（６１％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 461
Step 4.1-Synthesis of 1- [1- (4-chlorophenyl) piperidine-4-yl] -3- (5-hydroxypyridin-2-yl) urea

A 2N HCl aqueous solution (1 mL) was added dropwise to a solution of the product (180 mg, 0.39 mmol) from the previous step in THF (2 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (180 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 57.0% 30.0% ACN in 8 minutes); Purification by preparative-HPLC under conditions of detector, UV254 / 220 nm gave 82.8 mg (61%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 347
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.77 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 2.9 Hz) , 1H), 7.32 to 7.10 (m, 4H), 6.94 (d, J = 8.7Hz, 2H), 3.69 (s, 1H), 3.52 (m, 2H), 2.87 (m, 2H), 1.90 (m, 2H), 1.46 (m, 2H).

ステップ１．１－（４－フルオロフェニル）ピペリジン－４－オールの合成

ＤＭＳＯ（２０ｍＬ）中のピペリジン－４－オール（１ｇ、９．８９ｍｍｏｌ）、１－ブロモ－４－フルオロベンゼン（１．７４ｇ、９．９４ｍｍｏｌ）、Ｌ－プロリン（１．１５ｇ）、Ｋ_２ＣＯ_３（２．７６ｇ、１９．９７ｍｍｏｌ）、およびＣｕＩ（１９０ｍｇ、１．００ｍｍｏｌ）の溶液を、Ｎ_２下で、８０℃で１６時間攪拌し、次いで冷却し、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルカラムクロマトグラフィーで精製し、５００ｍｇ（２６％）の表題化合物をオフホワイトの固体として得た。 Scheme VII
Example 53
1- (4-Fluorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of 4- (4-fluorophenyl) piperidine-4-ol

Piperidine-4-ol (1 g, 9.89 mmol) in DMSO (20 mL), 1-bromo-4-fluorobenzene (1.74 g, 9.94 mmol), L-proline (1.15 g), K ₂ CO ₃ A solution of (2.76 g, 19.97 mmol) and CuI (190 mg, 1.00 mmol) was stirred under _N2 at 80 ° C. for 16 hours, then cooled and extracted with 2 x 60 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (2: 1) to give 500 mg (26%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 196
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 7.09 to 6.97 (m, 2H), 6.97 to 6.87 (m, 2H), 4.65 (d, J = 4.2 Hz, 1H), 4.09 (q, J = 5.3Hz, 1H), 3.41 (dt, J = 11.7, 4.3Hz, 2H), 3.16 (d, J = 5.1Hz, 2H) ), 2.76 (ddd, J = 12.7, 10.1, 3.1Hz, 2H), 1.46 (dtd, J = 13.0, 9.9, 3.8Hz, 2H).

攪拌したトリホスゲン（３８５ｍｇ、０．５０当量）を含むフラスコに、ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップから生成物（５００ｍｇ、２．５６ｍｍｏｌ、１．００当量）の溶液を、０℃で１分間にわたり滴下し、続いて、ピリジン（１ｍＬ）およびＣＨ_２Ｃｌ_２（１ｍＬ）の混合物を０℃で２分間にわたり攪拌しながら滴下した。混合物の温度を、ゆっくり室温に上昇させ、攪拌を２時間続けた。混合物に、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（５７４ｍｇ、２．５６ｍｍｏｌ、１．００当量）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、２００ｍｇ（１８％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 5- (4-fluorophenyl) piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

In a flask containing agitated triphosgene (385 mg, 0.50 eq), a solution of the product (500 mg, 2.56 mmol, 1.00 eq) from the previous step in CH ₂ Cl ₂ (10 mL) at 0 ° C. The mixture was added dropwise over 1 minute, followed by a mixture of pyridine (1 mL) and CH ₂ Cl ₂ (1 mL) at 0 ° C. for 2 minutes with stirring. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To the mixture was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (574 mg, 2.56 mmol, 1.00 eq). The resulting solution was stirred at room temperature for 16 hours and then extracted with 2 x 50 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 200 mg (18%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 446
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 7.88 (dd, J = 3.0, 0.6 Hz, 1H), 7.71 (d, J = 8. 9Hz, 1H), 7.32 (dd, J = 8.9, 3.0Hz, 1H), 7.01 (ddt, J = 19.6, 6.9, 2.4Hz, 4H), 4.83 (Dq, J = 8.5, 4.1Hz, 1H), 3.43 (d, J = 6.2Hz, 1H), 2.99 (ddd, J = 12.4, 8.9, 3.2Hz) , 3H) 1.99 (d, J = 4.5Hz, 2H), 1.82 to 1.65 (m, 2H), 0.96 (s, 9H), 0.19 (s, 6H).

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４５ｍｍｏｌ）、およびＢＵ_４ＮＦ（２３４ｍｇ、７．１３ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大５８．０％の２５．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、７５ ｍｇ（５０％）の表題化合物をオフホワイトの固体として得た。 Step 3.1 Synthesis of 1- (4-fluorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (200 mg, 0.45 mmol) from the previous step in THF (5 mL) and BU ₄ NF (234 mg, 7.13 mmol) was stirred at room temperature for 1 hour and then extracted with 20 mL EtOAc. bottom. The mixed organic layer was concentrated under vacuum. The crude product (200 mg) under the conditions of instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 58.0% 25.0% ACN in 7 minutes). Purification by preparative-HPLC gave 75 mg (50%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 332
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.51 (s, 1H), 7.79 (dd, J = 3.0, 0.7 Hz, 1H), 7 .59 (d, J = 8.8Hz, 1H), 7.16 (dd, J = 8.9, 3.0Hz, 1H), 7.08-6.89 (m, 4H), 4.79 ( dq, J = 8.5, 4.2Hz, 1H) 3.47 to 3.35 (m, 2H), 2.95 (ddd, J = 12.4, 9.1, 3.2Hz, 2H) 1.95 (s, 2H), 1.69 (dtd, J = 12.5, 8.8, 3.7Hz, 2H).

ステップ１．１－（２，４－ジフルオロフェニル）ピペリジン－４－オールの合成

ＤＭＳＯ（２０ｍＬ）中のピペリジン－４－オール（１ｇ、９．８９ｍｍｏｌ）、Ｌ－プロリン（１．１５ｇ）、Ｋ_２ＣＯ_３（２．７６ｇ、１９．９７ｍｍｏｌ）、２，４－ジフルオロ－１－ヨードベンゼン（２．４ｇ、１０．００ｍｍｏｌ）、およびＣｕＩ（１９０ｍｇ、１．００ｍｍｏｌ）の溶液を、Ｎ_２下で、８０℃で１６時間攪拌し、冷却した。得られた固体を、濾過により除去し、ＥｔＯＡｃで洗浄した。混合濾液を真空内で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、８００ｍｇ（３８％）の表題化合物をオフホワイトの固体として得た。 Example 54
1- (2,4-difluorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of (2,4-difluorophenyl) piperidine-4-ol

Piperidine-4-ol (1 g, 9.89 mmol) in DMSO (20 mL), L-proline (1.15 g), K2 CO _{3 (} 2.76 g, 19.97 mmol), 2,4-difluoro-1- A solution of iodobenzene (2.4 g, 10.00 mmol) and CuI (190 mg, 1.00 mmol) was stirred under _N2 at 80 ° C. for 16 hours and cooled. The resulting solid was removed by filtration and washed with EtOAc. The mixed filtrate was concentrated in vacuo and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 800 mg (38%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 214
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 7.21 to 6.91 (m, 3H), 4.68 (d, J = 4.2 Hz, 1H), 3.59 (dq, J = 8. 7, 4.4Hz, 1H), 3.14 (dt, J = 10.1, 4.2Hz, 2H), 2.75 to 2.67 (m, 2H), 1.86 to 1.80 (m). , 2H), 1.53 (ddt, J = 12.7, 9.2, 4.7Hz, 2H).

ＣＨ_２Ｃｌ_２（１０ｍＬ）中のトリホスゲン（３５２ｍｇ）、および前のステップからの生成物（５００ｍｇ、２．３４ｍｍｏｌ）の溶液に、ＣＨ_２Ｃｌ_２（１ｍＬ）中のピリジン（１ｍＬ）の溶液を０℃で加えた。混合物の温度をゆっくり室温に上昇させ、攪拌を２時間継続した。これに、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（５２５ｍｇ、２．３４ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌した。得られた溶液を、水でクエンチし、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、７２０ｍｇ（６６％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 5- (2,4-difluorophenyl) piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

0 solution of pyridine (1 mL) in CH ₂ Cl ₂ (1 mL) to solution of triphosgene (352 mg) in CH ₂ Cl ₂ (10 mL) and product from the previous step (500 mg, 2.34 mmol). Added at ° C. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To this was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (525 mg, 2.34 mmol). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was quenched with water and extracted with 2 x 50 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 720 mg (66%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 464
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 7.86 (dd, J = 3.0, 0.7 Hz, 1H), 7.73 to 7.64 (m, 1H), 7.30 (dd, J = 8.9, 3.0Hz, 1H), 7.25 to 6.93 (m, 3H), 4.79 (dt, J = 8.4, 4.3Hz) , 1H), 3.25 to 3.11 (m, 2H), 2.87 (t, J = 9.2Hz, 2H), 1.99 (s, 2H), 1.77 (td, J = 8) 8.8, 4.0Hz, 2H), 0.93 (s, 9H), 0.17 (s, 6H).

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（３００ｍｇ、０．６５ｍｍｏｌ）、およびＢｕ_４ＮＦ（３３７ｍｇ、１０．２７ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用してシリカゲルクロマトグラフィーで精製した。粗生成物（３００ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ４ＨＣＯ３）、およびＡＣＮ（７分間で最大５５．０％の３８．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４５．２ｍｇ（２０％）の表題化合物をオフホワイトの固体として得た。 Step 3.1 Synthesis of 1- (2,4-difluorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (300 mg, 0.65 mmol) from the previous step in THF (5 mL) and Bu ₄ NF (337 mg, 10.27 mmol) was stirred at room temperature for 1 hour and then extracted with 20 mL EtOAc. bottom. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using CH ₂ Cl ₂ / MeOH (20: 1). Crude product (300 mg), instrument "B"; column "A"; mobile phase, water (10 mM NH4HCO3), and ACN (up to 55.0% 38.0% ACN in 7 minutes); detector, Purification by preparative-HPLC under UV 254/220 nm conditions gave 45.2 mg (20%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 350
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.55 (s, 1H), 7.81 (d, J = 2.9Hz, 1H), 7.60 (d) , J = 8.9Hz, 1H), 7.26-7.16 (m, 2H), 7.16-7.09 (m, 1H), 7.09-6.93 (m, 1H), 4 .79 (tt, J = 8.2, 3.9Hz, 1H) 3.19 (dt, J = 11.0, 4.4Hz, 2H) 2.89 (td, J = 8.9, 4) .6Hz, 2H), 2.02 (d, J = 12.1Hz, 2H), 1.76 (dtd, J = 12.4, 8.6, 3.6Hz, 2H).

ステップ１．１－（４－クロロフェニル）ピペリジン－４－オールの合成

ＤＭＳＯ（２０ｍＬ）中の１－ブロモ－４－クロロベンゼン（７６０ｍｇ、３．９７ｍｍｏｌ）、Ｋ_２ＣＯ_３（１．１ｇ、７．９６ｍｍｏｌ）、ピペリジン－４－オール（４０４ｍｇ、３．９９ｍｍｏｌ）、Ｌ－プロリン（４６０ｍｇ）、およびＣｕＩ（７６ｍｇ、０．４０ｍｍｏｌ）の溶液を、Ｎ_２下で、８０℃で１６時間攪拌し、次いで冷却し、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、５６０ｍｇ（６７％）の表題化合物をオフホワイトの固体として得た。 Example 55
1- (4-chlorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of (4-chlorophenyl) piperidine-4-ol

1-bromo-4-chlorobenzene (760 mg, 3.97 mmol) in DMSO (20 mL), K2 CO ₃ (1.1 g, 7.96 mmol), piperidine- ₄ -ol (404 mg, 3.99 mmol), L- A solution of proline (460 mg) and CuI (76 mg, 0.40 mmol) was stirred under _N2 at 80 ° C. for 16 hours, then cooled and extracted with 2 x 60 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 560 mg (67%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 212
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 7.29 to 7.10 (m, 2H), 7.03 to 6.85 (m, 2H), 4.76 to 4.56 (m, 1H) 4.09 (s, 1H), 3.49 (dt, J = 12.7, 4.4Hz, 2H), 2.83 (ddd, J = 12.9, 10.0, 3.1Hz, 2H) ), 1.89 to 1.71 (m, 2H), 1.43 (dtd, J = 13.0, 9.8, 3.8 Hz, 2H).

ＣＨ_２Ｃｌ_２ （１０ｍＬ）中のトリホスゲン（３９８ｍｇ）の溶液に、ＣＨ_２Ｃｌ_２（１５ｍＬ）中の前のステップから生成物（５００ｍｇ、２．５６ｍｍｏｌ）の溶液を、１分間にわたり滴下し、続いて、ＣＨ_２Ｃｌ_２（１ｍＬ）中のピリジン（１ｍＬ）の溶液を、２分間にわたり攪拌しながら滴下した。混合物の温度をゆっくり室温に上昇させ、攪拌を２時間継続し、次いで、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（３００ｍｇ、１．３４ｍｍｏｌ）を加え、室温で１６時間攪拌を続けた。得られた溶液を、２×２０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、２８０ｍｇ（２３％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 5- (4-chlorophenyl) piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of the product (500 mg, 2.56 mmol) from the previous step in CH ₂ Cl ₂ (15 mL) was added dropwise to a solution of triphosgene (398 mg) in CH ₂ Cl ₂ (10 mL) over 1 minute, followed by Then, a solution of pyridine (1 mL) in CH ₂ Cl ₂ (1 mL) was added dropwise over 2 minutes with stirring. The temperature of the mixture was slowly raised to room temperature, stirring continued for 2 hours, then 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (300 mg, 1.34 mmol) was added and at room temperature for 16 hours. Stirring was continued. The resulting solution was extracted with 2 x 20 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to 280 mg (23%). The title compound was obtained as an off-white solid.

LC-MS: (ES, m / z): 462
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 7.88 (d, J = 2.9 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H) , 7.32 (dd, J = 9.0, 3.0Hz, 1H), 7.23 (d, J = 2.2Hz, 1H), 7.21 (d, J = 2.4Hz, 1H), 6.97 (td, J = 4.8, 2.5Hz, 2H), 4.85 (dt, J = 8.4, 4.4Hz, 1H), 3.57 to 3.48 (m, 2H) 3.25 to 2.82 (m, 2H), 1.98 (d, J = 9.4Hz, 2H), 1.92 to 1.47 (m, 2H), 0.95 (s, 9H) , 0.19 (s, 6H).

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（２８０ｍｇ、０．６１ｍｍｏｌ）、およびＢＵ_４ＮＦ（３１７ｍｇ、１．２１ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、混合し、真空下で濃縮した。粗生成物（２８０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大６４．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８１．２ｍｇ（３９％）の表題化合物をオフホワイトの固体として得た。 Step 3.1 Synthesis of 1- (4-chlorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (280 mg, 0.61 mmol) from the previous step in THF (5 mL) and BU ₄ NF (317 mg, 1.21 mmol) was stirred at room temperature for 1 hour and then extracted with 20 mL EtOAc. bottom. The mixed organic layer was mixed and concentrated under vacuum. Crude product (280 mg), instrument "B"; column "A"; mobile phase, water (0.1% FA) and ACN (up to 64.0% 35.0% ACN in 7 minutes); detector Purified by preparative-HPLC under UV254 / 220 nm conditions to give 81.2 mg (39%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 348
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.53 (s, 1H), 7.82-7.75 (m, 1H), 7.59 (d, J) = 8.9Hz, 1H), 7.26 to 7.11 (m, 3H), 7.01 to 6.90 (m, 2H), 4.80 (dt, J = 8.4, 4.3Hz, 1H), 3.54 to 3.42 (m, 2H), 3.10 to 2.95 (m, 2H), 1.93 (m, 2H), 1.68 (td, J = 8.8, 4.0Hz, 2H).

ステップ１．１－（５－フルオロピリジン－２－イル）ピペリジン－４－オールの合成

ＤＭＳＯ（２０ｍＬ）の２－ブロモ－５－フルオロピリジン（９００ｍｇ、５．１１ｍｍｏｌ）、ＣｕＩ（１００ｍｇ、０．５３ｍｍｏｌ）、プロリン（６００ｍｇ）、Ｋ_２ＣＯ_３（１．３８ｇ、９．９８ｍｍｏｌ）、およびピペリジン－４－オール（５１６ｍｇ、５．１１ｍｍｏｌ）の溶液を、８０℃で１ ６時間攪拌し、次いで２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、３００ｍｇ（３０％）の表題化合物をオフホワイトの固体として得た。 Example 56
1- (5-fluoropyridin-2-yl) piperidine-4-yl N- (5-hydroxypyridin-2-yl)

Step 1.1-Synthesis of 5- (5-fluoropyridin-2-yl) piperidine-4-ol

2-Bromo-5-fluoropyridine (900 mg, 5.11 mmol) in DMSO (20 mL), CuI (100 mg, 0.53 mmol), proline (600 mg), K2 CO _{3 (} 1.38 g, 9.98 mmol), and. A solution of piperidine-4-ol (516 mg, 5.11 mmol) was stirred at 80 ° C. for 16 hours and then extracted with 2 x 60 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 300 mg (30%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中のトリホスゲン（０．５当量）（３００ｍｇ）に、ＣＨ_２Ｃｌ_２（２ｍＬ）中の前のステップから生成物（３００ｍｇ、１．５３ｍｍｏｌ）の溶液を、０℃で１分間にわたり滴下し、続いて、ＣＨ_２Ｃｌ_２（２ｍＬ）中のピリジン（１ｍＬ）の溶液を、０℃で２分間にわたり攪拌しながら滴下した。混合物の温度を、ゆっくり室温に上昇させ、攪拌を２時間続けた。混合物に、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（１７１ｍｇ、０．７６ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、３０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×４０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、２００ｍｇ（２９％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 197
Step 2.1-Synthesis of piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of triphosgene (0.5 eq) (300 mg) in CH ₂ Cl ₂ (5 mL) to a solution of the product (300 mg, 1.53 mmol) from the previous step in CH ₂ Cl ₂ (2 mL) at 0 ° C. The solution was added dropwise over 1 minute, followed by a solution of pyridine (1 mL) in CH ₂ Cl ₂ (2 mL) at 0 ° C. for 2 minutes with stirring. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To the mixture was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (171 mg, 0.76 mmol). The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 30 mL _H2O and extracted with 2 x 40 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 200 mg (29%) of the title compound as an off-white solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４５ｍｍｏｌ）の溶液に、室温で２Ｎ ＨＣｌ水溶液（１ｍＬ）を少量ずつ加えた。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５６．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、３１．９ｍｇ（２１％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 447
Step 3.1 Synthesis of 1- (5-fluoropyridin-2-yl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A 2N HCl aqueous solution (1 mL) was added in small portions to a solution of the product (200 mg, 0.45 mmol) from the previous step in THF (2 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (200 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 56.0% 25.0% ACN in 8 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 31.9 mg (21%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 333.3
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.06 (d, J = 3.1 Hz, 1H), 7.78 ( d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.47 (ddd, J = 9.3, 8.3, 3.2 Hz, 1H), 7.16 (dd, J = 8.9, 3.0Hz, 1H), 6.89 (dd, J = 9.4, 3.4Hz, 1H), 4.85 (dt, J = 8.6) , 4.5Hz, 1H), 3.92 to 3.80 (m, 2H), 3.28 to 3.22 (m, 2H), 1.95 to 1.84 (m, 2H), 1.59 ~ 1.54 (m, 2H).

ステップ１．１－［４－（トリフルオロメチル）フェニル］ピペリジン－４－オールの合成

乾燥ＤＭＳＯ（２０ｍＬ）中の１－フルオロ－４－（トリフルオロメチル）ベンゼン（８２０ｍｇ、５．００ｍｍｏｌ）、ピペリジン－４－オール（５０５ｍｇ、４．９９ ｍｏｌ）、およびＤＩＥＡ（１．２９ｇ、９．９８ｍｍｏｌ）の溶液を、８０℃で１６時間攪拌し、次いで、室温に冷却し、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、４６０ｍｇ（３８％）の表題化合物をオフホワイトの固体として得た。 Example 57
1- [4- (trifluoromethyl) phenyl] piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of 4- (trifluoromethyl) phenyl] piperidine-4-ol

1-Fluoro-4- (trifluoromethyl) benzene (820 mg, 5.00 mmol) in dry DMSO (20 mL), piperidine-4-ol (505 mg, 4.99 mol), and DIEA (1.29 g, 9. The solution (98 mmol) was stirred at 80 ° C. for 16 hours, then cooled to room temperature and extracted with 2 × 60 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 460 mg (38%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 246
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 7.52 to 7.42 (m, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.70 (d, J = 4. 3Hz, 1H), 4.09 (q, J = 5.3Hz, 1H), 3.66 (dd, J = 8.7, 4.4Hz, 2H), 2.99 (ddd, J = 13.1) , 9.9, 3.1 Hz, 2H), 1.86 to 1.68 (m, 2H), 1.41 (dtd, J = 12.9, 9.5, 3.8 Hz, 2H).

ＣＨ_２Ｃｌ_２（５ｍＬ）中のトリホスゲン（２８０ｍｇ）に、ＣＨ_２Ｃｌ_２（２ｍＬ）中の前のステップから生成物（４６０ｍｇ、１．８８ｍｍｏｌ）の溶液を、０℃で１分間にわたり滴下し、続いて、ピリジン（１ｍＬ）およびＣＨ_２Ｃｌ_２（１ｍＬ）の混合物を、０℃で２分間にわたり攪拌しながら滴下した。混合物の温度を、ゆっくり室温に上昇させ、攪拌を２時間続けた。混合物に、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ、０．６０当量）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２×６０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、２６０ｍｇ（２８％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 4- [4- (trifluoromethyl) phenyl] piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of the product (460 mg, 1.88 mmol) from the previous step in CH ₂ Cl ₂ (2 mL) was added dropwise to triphosgene (280 mg) in CH ₂ Cl ₂ (5 mL) at 0 ° C. over 1 minute. Subsequently, a mixture of pyridine (1 mL) and CH ₂ Cl ₂ (1 mL) was added dropwise at 0 ° C. for 2 minutes with stirring. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To the mixture was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (224 mg, 1.00 mmol, 0.60 eq). The resulting solution was stirred at room temperature for 16 hours and then extracted with 2 x 60 mL CH ₂ Cl ₂ . The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 260 mg (28%) of the title compound as an off-white solid.

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（２６０ｍｇ、０．５２ｍｍｏｌ）の溶液に、室温でＢｕ_４ＮＦ（２７４ｍｇ）を加えた。得られた溶液を、室温で２時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、真空下で濃縮した。粗生成物（２６０ｍｇ）を、機器「Ｂ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６５．０％の３５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５４．８ ｍｇ（２７％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 496
Step 3.1-Synthesis of 4- (trifluoromethyl) phenyl] piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Bu ₄ NF (274 mg) was added to a solution of the product (260 mg, 0.52 mmol) from the previous step in THF (5 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum. Crude product (260 mg), instrument "B"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 65.0% 35.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 54.8 mg (27%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 382
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.53 (s, 1H), 7.79 (d, J = 3.0Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.47 (d, J = 8.5Hz, 2H), 7.17 (dd, J = 8.9, 3.0Hz, 1H), 7.06 (d, J = 8.6Hz, 2H), 4.86 (dt, J = 8.2, 4.8Hz, 1H), 3.70 to 3.58 (m, 2H), 3.27 to 3.12 (m). , 2H), 1.93 (s, 2H), 1.64 (m, 2H).

ステップ１．１－（２，４－ジクロロフェニル）ピペリジン－４－オールの合成

乾燥ＤＭＳＯ（２０ｍＬ）中のピペリジン－４－オール（１．０１ｇ、９．９９ｍｍｏｌ）、２，４－ジクロロ－１－フルオロベンゼン（１．６５ｇ、１０．００ｍｍｏｌ）、およびＤＩＥＡ（２．５８ｇ）の溶液を、８０℃で１６時間攪拌し、次いで冷却し、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、１１０ｍｇ（４％）の表題化合物をオフホワイトの固体として得た。 Example 58
1- (2,4-dichlorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of (2,4-dichlorophenyl) piperidine-4-ol

Piperidine-4-ol (1.01 g, 9.99 mmol), 2,4-dichloro-1-fluorobenzene (1.65 g, 10.00 mmol), and DIEA (2.58 g) in dry DMSO (20 mL). The solution was stirred at 80 ° C. for 16 hours, then cooled and extracted with 2 x 50 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 110 mg (4%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 246
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.14 ( d, J = 8.7Hz, 1H), 4.70 (d, J = 4.2Hz, 1H), 3.61 (tt, J = 8.6, 4.3Hz, 1H), 3.13 (dt) , J = 10.2, 4.2Hz, 2H) 2.70 (ddd, J = 12.1, 9.7, 2.9Hz, 2H), 1.91 to 1.72 (m, 2H), 1.54 (dtd, J = 12.7, 9.2, 3.6 Hz, 2H).

ＣＨ_２Ｃｌ_２（５ｍＬ）中のトリホスゲン（６７ｍｇ）に、ＣＨ_２Ｃｌ_２（１ｍＬ）中の前のステップから生成物（１１０ｍｇ、０．４５ｍｍｏｌ）の溶液を、１分間にわたり攪拌しながら滴下し、続いて、ＣＨ_２Ｃｌ_２（０．５ｍＬ）中のピリジン（０．５ｍＬ）の溶液を、１分間にわたり攪拌しながら滴下した。混合物の温度を、ゆっくり室温に上昇させ、攪拌を２時間続けた。混合物に、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（１００ｍｇ、０．４５ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１６０ｍｇ（７２％）の表題化合物をオフホワイトの固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４９６。 Step 2.1-Synthesis of (2,4-dichlorophenyl) piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of the product (110 mg, 0.45 mmol) from the previous step in CH ₂ Cl ₂ (1 mL) was added dropwise to triphosgene (67 mg) in CH ₂ Cl ₂ (5 mL) with stirring over 1 minute. Subsequently, a solution of pyridine (0.5 mL) in CH ₂ Cl ₂ (0.5 mL) was added dropwise over 1 minute with stirring. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To the mixture was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (100 mg, 0.45 mmol). The resulting solution was stirred at room temperature for 16 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 2) to give 160 mg (72%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 496.

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（１６０ｍｇ、０．３２ｍｍｏｌ）、およびＢｕ_４ＮＦ（１６９ｍｇ、０．６５ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、２０ｍＬのＨ_２Ｏで希釈し、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮した。粗生成物（１６０ｍｇ）を、機器「Ａ」；カラム「Ｅ」；移動相、水（０．０５％ＴＦＡ）およびＡＣＮ（７分間で最大３７．０％の５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５８．３ｍｇ（４７％）の表題化合物をオフホワイトの固体として得た。 Step 3.1 Synthesis of 1- (2,4-dichlorophenyl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (160 mg, 0.32 mmol) from the previous step in THF (5 mL) and Bu ₄ NF (169 mg, 0.65 mmol) was stirred at room temperature for 1 hour, then 20 mL H ₂ O. Diluted with 2 x 30 mL of EtOAc and extracted. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. Crude product (160 mg), instrument "A"; column "E"; mobile phase, water (0.05% TFA) and ACN (up to 37.0% 5.0% ACN in 7 minutes); detector Purified by preparative-HPLC under UV254 / 220 nm conditions to give 58.3 mg (47%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 382
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 9.55 (s, 1H), 7.79 (d, J = 2.9Hz, 1H), 7.59 (d) , J = 8.9Hz, 1H), 7.52 (d, J = 2.5Hz, 1H), 7.35 (dd, J = 8.6, 2.5Hz, 1H), 7.25-7. 0 (m, 2H), 4.80 (tt, J = 8.1, 3.9Hz, 1H), 3.23 to 3.09 (m, 2H), 2.86 (ddd, J = 11.8) , 8.6, 3.1Hz, 2H), 2.00 (ddt, J = 10.0, 6.9, 4.2Hz, 2H), 1.75 (dtd, J = 12.2, 8.4) , 3.5Hz, 2H).

ステップ１．１－（ピリジン－２－イル）ピペリジン－４－オールの合成

ＤＭＳＯ（３０ｍＬ）中の２－フルオロピリジン（９７０ｍｇ、９．９９ｍｍｏｌ）、ピペリジン－４－オール（１．０１ｇ、９．９９ｍｍｏｌ）、およびＫ_２ＣＯ_３（２．７６ｇ、１９．９７ｍｍｏｌ）の混合物を、室温で１６時間攪拌し、次いで、２×１００ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、６９０ｍｇ（３９％）の表題化合物をオフホワイトの固体として得た。 Example 59
1- (Pyridine-2-yl) piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

Step 1.1-Synthesis of Piperidine-4-ol (Pyridine-2-yl)

A mixture of _{2-fluoropyridine (970 mg, 9.99 mmol), piperidine-4-ol (1.01 g, 9.99 mmol) and K2 CO 3 (} 2.76 g, 19.97 mmol) in DMSO (30 mL). The mixture was stirred at room temperature for 16 hours and then extracted with 2 x 100 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 690 mg (39%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 179
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (ddd, J = 4.9, 2.1, 0.9 Hz, 1H), 7.49 (ddd, J = 8.9, 7.1) , 2.1Hz, 1H), 6.81 (dd, J = 8.6, 0.9Hz, 1H), 6.57 (ddd, J = 7.1, 4.8, 0.8Hz, 1H), 4.67 (d, J = 4.3Hz, 1H), 4.04 to 3.93 (m, 2H), 3.69 (tq, J = 8.5, 4.1Hz, 1H), 3.05 (Ddd, J = 13.3, 10.2, 3.1Hz, 2H) 1.76 (dqd, J = 10.0, 3.6, 1.7Hz, 2H), 1.40 to 1.29 (M, 2H).

ＣＨ_２Ｃｌ_２（１０ｍＬ）中のトリホスゲン（５８１ｍｇ）に、ＣＨ_２Ｃｌ_２（２ｍＬ）中の前のステップから生成物（６９０ｍｇ、３．８７ｍｍｏｌ）の溶液を、１分間にわたり攪拌しながら滴下し、続いて、ＣＨ_２Ｃｌ_２（１ｍＬ）中のピリジン（１ｍＬ）の溶液を、２分間にわたり攪拌しながら滴下した。混合物の温度を、ゆっくり室温に上昇させ、攪拌を２時間続けた。混合物に、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（３００ｍｇ、１．３４ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌した。得られた溶液を、２×５０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、５００ｍｇ（３０％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of the product (690 mg, 3.87 mmol) from the previous step in CH ₂ Cl ₂ (2 mL) was added dropwise to triphosgene (581 mg) in CH ₂ Cl ₂ (10 mL) with stirring over 1 minute. Subsequently, a solution of pyridine (1 mL) in CH ₂ Cl ₂ (1 mL) was added dropwise over 2 minutes with stirring. The temperature of the mixture was slowly raised to room temperature and stirring was continued for 2 hours. To the mixture was added 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (300 mg, 1.34 mmol). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with 2 x 50 mL CH ₂ Cl ₂ , the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to 500 mg (30). %) The title compound was obtained as an off-white solid.

LC-MS: (ES, m / z): 429
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.09 (ddd, J = 4.9, 2.1, 0.8 Hz, 1H), 7.94-7 .81 (m, 1H), 7.77-7.66 (m, 1H), 7.50 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.38-7 .28 (m, 1H), 6.85 (d, J = 8.6Hz, 1H), 6.59 (ddd, J = 7.1, 4.9, 0.8Hz, 1H), 4.88 (Dt, J = 8.5, 4.4Hz, 1H) 4.02 to 3.86 (m, 2H), 3.31 (m, 2H), 1.92 (d, J = 12.9Hz, 2H), 1.57 (dtd, J = 12.7, 8.8, 3.8 Hz, 2H), 0.93 (d, J = 2.7 Hz, 9H), 0.17 (d, J = 3.6Hz, 6H).

前のステップからの生成物（２５０ｍｇ、０．５８ｍｍｏｌ）、およびＢｕ_４ＮＦ（３０４ｇ、１．１６ｍｏｌ）、ＴＨＦ（６ｍＬ）の溶液を、室温で１時間攪拌し、次いで、３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用してシリカゲルクロマトグラフィーで精製した。粗生成物（２５０ｍｇ）を、機器「Ｂ」；カラム「Ｄ」；移動相、１ ０ｍＭ ＮＨ４ＨＣＯ３水溶液、およびＡＣＮ（７分間で最大５０．０％の８．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８３ｍｇ（４５％）の表題化合物をオフホワイトの固体として得た。 Step 3.1-Synthesis of piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product from the previous step (250 mg, 0.58 mmol) and Bu ₄ NF (304 g, 1.16 mol), THF (6 mL) was stirred at room temperature for 1 hour and then extracted with 30 mL EtOAc. .. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using CH ₂ Cl ₂ / MeOH (20: 1). Crude product (250 mg), instrument "B"; column "D"; mobile phase, 10 mM NH4HCO3 aqueous solution, and ACN (up to 50.0% 8.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 83 mg (45%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 315
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.70 (s, 1H), 9.52 (s, 1H), 8.09 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.50 (ddd, J = 8.9, 7.1, 2.1Hz, 1H), 7.16 (dd, J = 8.9, 3.0Hz, 1H), 6.89-6.79 (m, 1H), 6.59 (ddd, J = 7. 1,4.8, 0.8Hz, 1H), 4.87 (tt, J = 8.3, 3.9Hz, 1H), 3.94 (dt, J = 13.3, 4.8Hz, 2H) 3.36 to 3.21 (m, 2H), 1.98 to 1.83 (m, 2H), 1.56 (dtd, J = 12.7, 8.8, 3.7Hz, 2H).

ステップ１．１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペリジン－４－オールの合成

ＮＭＰ（１０ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン（１．８ｇ、９．９２ｍｍｏｌ）、ピペリジン－４－オール（１ｇ、９．８９ｍｍｏｌ）、およびＤＩＥＡ（２．６ｇ、２０．１２ｍｍｏｌ）の溶液を、１６０℃で１．５時間攪拌した。反応混合物を冷却し、水を加えた。次いで、混合物を２×５０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空内で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、１．２ｇ（４９％）の表題化合物を固体として得た。 Example 60
1- [5- (Trifluoromethyl) Pyridine-2-yl] Piperidine-4-yl N- (5-Hydroxypyridin-2-yl) Carbamate

Step 1.1-Synthesis of 5- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-ol

2-Chloro-5- (trifluoromethyl) pyridine (1.8 g, 9.92 mmol) in NMP (10 mL), piperidine-4-ol (1 g, 9.89 mmol), and DIEA (2.6 g, 20. The solution (12 mmol) was stirred at 160 ° C. for 1.5 hours. The reaction mixture was cooled and water was added. The mixture was then extracted with 2 x 50 mL EtOAc, the mixed organic layer was concentrated in vacuo and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to 1.2 g (49%). The title compound was obtained as a solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中のトリホスゲン（０．５当量）（３００ｍｇ、１．００当量）に、ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップから生成物（４９２ｍｇ、２．００ｍｍｏｌ）の溶液を、０℃で攪拌しながら滴下し、続いて、ＣＨ_２Ｃｌ_２（５ｍＬ）中のピリジン（１ｍＬ）を、０℃で攪拌しながら滴下し、続いて５－［（ｔｅｒｔ－ブチルジメチルシリル）－オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ）を加えた。得られた溶液を、室温で１６時間攪拌し、次いで、１０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（２：１）を使用してシリカゲルクロマトグラフィーで精製し、１００ｍｇ（１０％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 247
Step 2.1-Synthesis of 5- [5- (trifluoromethyl) pyridin-2-yl] piperidine-4-yl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] carbamate

A solution of triphosgene (0.5 eq) (300 mg, 1.00 eq) in CH ₂ Cl ₂ (5 mL) to the product (492 mg, 2.00 mmol) from the previous step in CH ₂ Cl ₂ (5 mL). Was added dropwise at 0 ° C. with stirring, and then pyridine (1 mL) in CH ₂ Cl ₂ (5 mL) was added dropwise at 0 ° C. with stirring, followed by 5-[(tert-butyldimethylsilyl). -Oxy] Pyridine-2-amine (224 mg, 1.00 mmol) was added. The resulting solution was stirred at room temperature for 16 hours, then quenched by the addition of 10 mL _H2O and extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (2: 1) to give 100 mg (10%) of the title compound as an off-white solid.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．２０ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１００ｍｇ）を、
機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大５７．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２３ｍｇ（３０％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 497
Step 3.1-Synthesis of 5- (trifluoromethyl) pyridine-2-yl] piperidine-4-yl N- (5-hydroxypyridin-2-yl) carbamate

A solution of the product (100 mg, 0.20 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (100 mg),
Instrument "A"; Column "A"; Mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 57.0% 30.0% ACN in 8 minutes); Detector, UV254 / 220 nm. Purification by preparative-HPLC gave 23 mg (30%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 383.0
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 9.72 (s, 1H), 9.54 (s, 1H), 8.39 (s, 1H), 7.79-7.76 (m, 2H) ), 7.59 (d, J = 8.9 Hz, 1H), 7.16 (dd, J = 8.9, 3.0 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H). ), 4.91 (dt, J = 8.0, 4.5 Hz, 1H), 4.00 (d, J = 13.6 Hz, 2H), 3.55-3.42 (m, 2H) 1.99 to 1.91 (m, 2H), 1.64 to 1.50 (m, 2H).

ステップ１：Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（プロパン－２－イル）ベンゼン－１－スルホンアミドの合成

５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ、１．００当量）、４－（プロパン－２－イル）ベンゼン－１－スルホニルクロリド（２１８ｍｇ、１．００ｍｍｏｌ、１．００当量）、およびピリジン（４ｍＬ）の溶液を、室温で４時間攪拌した。得られた混合物を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、３００ｍｇ（７４％）の表題化合物を白色固体として得た。 Scheme VIII
Example 61
N- (5-Hydroxypyridin-2-yl) -4- (Propane-2-yl) Benzene-1-sulfonamide

Step 1: Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (propane-2-yl) benzene-1-sulfonamide

5-[(tert-butyldimethylsilyl) oxy] Pyridine-2-amine (224 mg, 1.00 mmol, 1.00 eq), 4- (propane-2-yl) benzene-1-sulfonyl chloride (218 mg, 1. A solution of 00 mmol (1.00 eq), and pyridine (4 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 300 mg (74%) of the title compound as a white solid.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップから生成物（３００ｍｇ、０．７４ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで真空下で濃縮し、機器「Ｂ」；カラム、ＳｕｎＦｉｒｅ Ｃ１８ ＯＢＤ分取カラム、１００＆＃６５５３３；、５ｐｍ、１９ｍｍＸ２５０ｍｍ；移動相、水（０．１％ＦＡ）、およびＡＣＮ（７分間で最大６８．０％の３５．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１３７ｍｇ（６４％）の表題化合物を白色固体として得た。 LC-MS (ES, m / z): 406
Step 2: Synthesis of N- (5-hydroxypyridin-2-yl) -4- (propane-2-yl) benzene-1-sulfonamide

A solution of the product (300 mg, 0.74 mmol, 1.00 equivalent) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours, then concentrated under vacuum and instrumented. "B"; column, SunFire C18 OBD preparative column, 100 � 5pm, 19mmX250mm; mobile phase, water (0.1% FA), and ACN (up to 68.0% in 7 minutes, 35.0%). ACN); detector, purified by preparative-HPLC under uv254 / 220 nm conditions to give 137 mg (64%) of the title compound as a white solid.

LC-MS: (ES, m / z): 292
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.64 (s, 1H), 7.79-7.70 (m, 3H), 7.41 (d, J) = 8.3Hz, 2H), 7.15 (d, J = 8.8, 3.0Hz, 1H), 7.04 (d, J = 8.8Hz, 1H), 2.94 (m, 1H) , 1.19 (d, 7 = 6Hz, 6H).

ステップ１：４－ｔｅｒｔ－ブチル－Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ベンゼン－１－スルホンアミドの合成

ピリジン（５ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ、１．００当量）、および４－ｔｅｒｔ－ブチルベンゼン－１－スルホニルクロリド（２３２ｍｇ、１．００ｍｍｏｌ、１．００当量）の溶液を、室温で４時間攪拌した。得られた混合物を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：２）を使用してシリカゲルクロマトグラフィーで精製し、２３０ｍｇ（５５％）の表題化合物を白色固体として得た。 Example 62
4-tert-Butyl-N- (5-hydroxypyridin-2-yl) benzene-1-sulfonamide

Step 1: Synthesis of 4-tert-butyl-N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] benzene-1-sulfonamide

5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (224 mg, 1.00 mmol, 1.00 eq) in pyridine (5 mL), and 4-tert-butylbenzene-1-sulfonyl chloride (232 mg). , 1.00 mmol, 1.00 eq) was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 2) to give 230 mg (55%) of the title compound as a white solid.

２Ｎ ＨＣｌ（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（２３０ｍｇ、０．５５ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物を、機器「Ｂ」；カラム、ＳｕｎＦｉｒｅ Ｃ１８ ＯＢＤ分取カラム、１００＆＃６５５３３；、５μｍ、１９ｍｍＸ２５０ｍｍ；移動相、水（０．１％ＦＡ）、およびＡＣＮ（７分間で最大８０．０％の３０．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１２８．２ｍｇ（７７％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 421
Step 2: Synthesis of 4-tert-butyl-N- (5-hydroxypyridin-2-yl) benzene-1-sulfonamide

A solution of the product (230 mg, 0.55 mmol, 1.00 eq) from the previous step in 2N HCl (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product, instrument "B"; column, SunFire C18 OBD preparative column, 100 � 5 μm, 19 mmX250 mm; mobile phase, water (0.1% FA), and ACN (up to 80.0 in 7 minutes). % 30.0% ACN); detector, purified by preparative-HPLC under uv254 / 220 nm conditions to give 128.2 mg (77%) of the title compound as a white solid.

LC-MS: (ES, m / z): 306
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.64 (s, 1H), 7.78 to 7.72 (m, 2H), 7.61 to 7.54 (M, 2H), 7.15 (dd, J = 8.8, 3.0Hz, 1H), 7.04 (d, J = 8.8Hz, 1H), 1.27 (s, 9H).

ステップ１．ベンジル４－（［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］スルファモイル）ピペリジン－１－カルボキシレートの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（１０５ｍｇ、０．４７ｍｍｏｌ）、Ｅｔ_３Ｎ（１５０ｍｇ、１ ４８ｍｍｏｌ）の溶液に、ベンジル４－（クロロスルホニル）－ピペリジン－１－カルボキシレート（１５０ｍｇ、０．４７ｍｍｏｌ）を、０℃で少量ずつ加えた。得られた溶液を室温で２時間攪拌し、次いで、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１８０ｍｇ（７５％）の表題化合物をオフホワイトの固体として得た。 Example 63
Benzyl 4- [(5-hydroxypyridin-2-yl) sulfamoyl] piperidine-1-carboxylate

Step 1. Synthesis of benzyl4-([5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] sulfamoyl) piperidine-1-carboxylate

Benzyl4- in a solution of 5-[(tert-butyldimethylsilyl) oxy] pyridin- ₂ -amine (105 mg, 0.47 mmol), Et 3N (150 mg, 148 mmol) in CH ₂ Cl ₂ (5 mL). (Chlorosulfonyl) -piperidine-1-carboxylate (150 mg, 0.47 mmol) was added in small portions at 0 ° C. The resulting solution was stirred at room temperature for 2 hours and then extracted with 2 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1/2) to give 180 mg (75%) of the title compound as an off-white solid.

ＴＨＦ（５ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３６ｍｍｏｌ）、およびＢｕ_４（１８６ｍｇ、０．７１ｍｍｏｌ）の溶液を、室温で１時間攪拌し、次いで、２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ４ＨＣＯ３）、およびＡＣＮ（８分間で最大４６．０％の２８．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、７１．５ｍｇの表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 506
Step 2. Synthesis of benzyl 4-[(5-hydroxypyridin-2-yl) sulfamoyl] piperidine-1-carboxylate

A solution of the product (180 mg, 0.36 mmol) from the previous step in THF (5 mL) and Bu ₄ (186 mg, 0.71 mmol) was stirred at room temperature for 1 hour and then extracted with 20 mL EtOAc. .. The mixed organic layer was concentrated under vacuum. The crude product (180 mg) under the conditions of instrument "A"; column "A"; mobile phase, water (10 mM NH4HCO3), and ACN (up to 46.0% 28.0% ACN in 8 minutes). Purification by preparative-HPLC gave 71.5 mg of the title compound as an off-white solid.

LC-MS: (ES, m / z): 392
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.80 (s, 2H), 7.80 (d, J = 2.9 Hz, 1H), 7.42 to 7.24 (m, 5H), 7 .16 (dd, J = 8.8, 3.0Hz, 1H), 6.92 (d, J = 8.7Hz, 1H), 5.06 (s, 2H), 4.06 (d, J = 13.2Hz, 2H), 3.64-3.56 (m, 1H), 2.84 (s, 2H), 1.99m, 2H), 1.51 (m, 2H).

ステップ１．ベンジル４－（［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］スルファモイル）ピペリジン－１－カルボキシレートの合成

５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２．１ｇ、９．３６ｍｍｏｌ）およびＥｔ_３Ｎ（２．８ｇ、２８．４６ｍｍｏｌ）の混合物に、ＣＨ_２Ｃｌ_２（３０ｍＬ）中のベンジル４－（クロロスルホニル）ピペリジン－１－カルボキシレート（３ｇ、９．４４ｍｍｏｌ）の溶液を、０℃で２分間にわたり加えた。得られた溶液を、０℃で２時間攪拌し、次いで、５０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×１００ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、３．２ｇ（６７％）の表題化合物をオフホワイトの固体として得た。 Example 64
N- (5-Hydroxypyridin-2-yl) -1-phenylpiperidine-4-sulfonamide

Step 1. Synthesis of benzyl4-([5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] sulfamoyl) piperidine-1-carboxylate

CH ₂ Cl ₂ (30 mL) in a mixture of 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-amine (2.1 g, 9.36 mmol) and Et ₃ N (2.8 g, 28.46 mmol). A solution of benzyl4- (chlorosulfonyl) piperidine-1-carboxylate (3 g, 9.44 mmol) in was added at 0 ° C. for 2 minutes. The resulting solution was stirred at 0 ° C. for 2 hours, then quenched by the addition of 50 mL _H2O and extracted with 2 x 100 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 3.2 g (67%) of the title compound as an off-white solid.

ＭｅＯＨ（３０ｍＬ）中の前のステップからの生成物（３．２ｇ、６．３３ｍｍｏｌ）の溶液を、Ｈ_２大気下でＰｄ／Ｃ（３００ｍｇ）で２時間攪拌し、次いで真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＭｅＯＨ（２０：１）を使用してシリカゲルクロマトグラフィーで精製し、１．２６ｇ（５４％）の表題化合物を淡褐色固体として得た。 LC-MS: (ES, m / z): 506
Step 2. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide

A solution of the product (3.2 g, 6.33 mmol) from the previous step in MeOH (30 mL) was stirred with Pd / C (300 mg) for ₂ hours under H2 atmosphere and then concentrated under vacuum. Purification by silica gel chromatography using CH ₂ Cl ₂ / MeOH (20: 1) gave 1.26 g (54%) of the title compound as a light brown solid.

LC-MS: (ES, m / z): 372
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 7.86 (d, J = 2.9 Hz, 1H), 7.28 (dd, J = 8.8, 3.0Hz, 1H), 6.95 (D, J = 8.8 Hz, 1H), 3.53 (t, J = 11.9 Hz, 1H), 3.20 to 2.99 (m, 2H), 2.59 to 2.51 ( m, 2H), 1.93 (d, J = 12.5 Hz, 2H), 1.60 (qd, J = 12.1, 3.9 Hz, 2H), 0.93 (s, 9H), 0.17 (s, 6H).

トルエン（５ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．５４ｍｍｏｌ）、ＣＳ_２ＣＯ_３（３５２ｍｇ、１．０８ｍｍｏｌ）、ブロモベンゼン（１．６８ｇ、１０．７０ｍｍｏｌ）、ＲｕＰｈｏｓ（２６ｇ）、および３Ｇ ＲｕＰｈｏｘ Ｐｄ触媒（４５ｍｇ）の混合物を、１００℃で１６時間攪拌し、次いで、２０ｍＬのＨ_２Ｏを加えることによりクエンチし、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、３０ｍｇ（１２％）の表題化合物をオフホワイトの固体として得た。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1-phenylpiperidine-4-sulfonamide

Products from the previous step in toluene (5 mL) (200 mg, 0.54 mmol), CS ₂ CO ₃ (352 mg, 1.08 mmol), bromobenzene (1.68 g, 10.70 mmol), RuPhos (26 g), A mixture of and 3G RuPhox Pd catalyst (45 mg) was stirred at 100 ° C. for 16 hours, then quenched by the addition of 20 mL _H2O and extracted with 2 x 60 mL EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1/2) to give 30 mg (12%) of the title compound as an off-white solid.

２Ｎ ＨＣｌ（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（３０ｍｇ、０．０７ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（３０ｍｇ）を、機器「Ａ」；カラム「Ｅ」；移動相、１ ０ｍＭ ＮＨ４ＨＣＯ３ 水溶液、およびＡＣＮ（７分間で最大５０．０％の２０．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、８．７ｍｇ（３９％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 448
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -1-phenylpiperidine-4-sulfonamide

A solution of the product (30 mg, 0.07 mmol) from the previous step in 2N HCl (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (30 mg) was fractionated under the conditions of instrument "A"; column "E"; mobile phase, 10 mM NH4HCO3 aqueous solution, and ACN (up to 50.0% 20.0% ACN in 7 minutes). Purification by HPLC gave 8.7 mg (39%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 334
^{1 1} H NMR (300Mhz, methanol-d ₄ ) δ 7.78 (d, J = 2.9Hz, 1H), 7.28-7.11 (m, 3H), 7.05 (dd, J = 8. 8, 0.7Hz, 1H), 7.02 to 6.92 (m, 2H), 6.82 (t, J = 7.4Hz, 1H), 3.77 (d, J = 12.6Hz, 2H), 3.45 (tt, J = 12.0, 3.8 Hz, 1H), 2.70 (m, 2H), 2.19 (d, J = 12.6 Hz, 2H), 1. 94 (m, 2H).

ステップ１．１－ベンジル－Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－４－スルホンアミドの合成

ＤＭＦ（１０ｍＬ）中のＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－４－スルホンアミド（６００ｍｇ、１．６１ｍｍｏｌ、１．００当量）、（ブロモメチル）ベンゼン（２４７ｍｇ、１．４４ｍｍｏｌ、０．９０当量）、およびＤＩＥＡ （２０８ｍｇ、１．６１ｍｍｏｌ、１．００当量）の溶液を、０℃で２時間攪拌し、次いでＨ_２ Ｏでクエンチし、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、６７０ｍｇ（９０％）の表題化合物をオフホワイトの固体として得た。 Example 65
1-Benzyl-N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

Step 1.1-Synthesis of 5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide

N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide (600 mg, 1.61 mmol, 1.00 eq), (bromomethyl) benzene in DMF (10 mL) A solution of (247 mg, 1.44 mmol, 0.90 eq) and DIEA (208 mg, 1.61 mmol, 1.00 eq) was stirred at 0 ° C. for 2 hours, then quenched with H2O and ₂ × 30 mL. Extracted with EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1/2) to give 670 mg (90%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 462
^{1 1} H NMR (400Mhz, DMSO-d ₆ ) δ 10.23 (s, 1H), 7.95 (s, 1H), 7.92-7.86 (m, 1H), 7.36-7.19 (M, 6H), 6.97 (dd, J = 8.7, 0.6 Hz, 1H), 3.45 (s, 2H), 2.73 (d, J = 0.6Hz, 4H), 1.92 (s, 2H), 1.74-1.60 (m, 2H), 0.94 (s, 9H), 0.19 (s, 6H).

２Ｎ ＨＣｌ（１ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（２００ｍｇ、０．４３ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４７．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７８．２ ｍｇ（５２％）の表題化合物をオフホワイトの固体として得た。 Step 2.1 Synthesis of benzyl-N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

A solution of the product (200 mg, 0.43 mmol, 1.00 eq) from the previous step in 2N HCl (1 mL) and THF (4 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (200 mg), instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 47.0% 20.0% ACN in 8 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 78.2 mg (52%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 348
^{1 1} H NMR (400 Mhz, DMSO-d ₆ ) δ 9.70 (br, 2H), 7.82 (d, J = 2.9 Hz, 1H), 7.39 to 7.21 (m, 5H), 7 .16 (dd, J = 8.8, 2.9Hz, 1H), 6.93 (d, J = 8.8Hz, 1H), 3.45 (s, 2H), 3.31 (m, 1H) 2.88 (m, 2H), 1.91 (m, 4H), 1.65 (m, 2H).

ステップ１．ベンジル４－（［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］スルファモイル）ピペリジン－１－カルボキシレートの合成

ＣＨ_２Ｃｌ_２（８０ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（４．３８ｇ、１９．５２ｍｍｏｌ）、およびＥｔ_３Ｎ（５．９ｇ、５８．３１ｍｍｏｌ）の溶液に、ＣＨ_２Ｃｌ_２（２０ｍＬ）中のベンジル４－（クロロスルホニル）ピペリジン－１－カルボキシレート（６．２ｇ、１９．５１ｍｍｏｌ）の溶液を、０℃で３分間にわたり攪拌しながら滴下した。得られた溶液を、０℃で２時間攪拌し、次いで、減圧下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用したシリカゲルクロマトグラフィーで精製した。得られた溶液を２×２００ｍＬのＣＨ_２Ｃｌ_２で抽出し、有機層を混合し、真空下で濃縮した。これにより、６．２ｇ（６３％）の表題化合物をオフホワイトの固体として得た。 Example 66
1- (4-fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

Step 1. Synthesis of benzyl4-([5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] sulfamoyl) piperidine-1-carboxylate

5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (4.38 g, 19.52 mmol) in CH ₂ Cl ₂ (80 mL), and Et 3N (5.9 g, _58.31 mmol). A solution of benzyl4- (chlorosulfonyl) piperidine-1-carboxylate (6.2 g, 19.51 mmol) in CH ₂ Cl ₂ (20 mL) was added dropwise to the solution at 0 ° C. for 3 minutes with stirring. The resulting solution was stirred at 0 ° C. for 2 hours, then concentrated under reduced pressure and purified by silica gel chromatography using EtOAc / Hexanes (1/2). The resulting solution was extracted with 2 x 200 mL CH ₂ Cl ₂ , mixed with an organic layer and concentrated under vacuum. This gave 6.2 g (63%) of the title compound as an off-white solid.

ＭｅＯＨ（６０ｍＬ）中の前のステップからの生成物（６ｇ、１１．８６ｍｍｏｌ）の溶液を、Ｈ２下で、Ｐｄ／Ｃ（６００ｍｇ）で１時間攪拌した。固体を濾過により除去し、濾液を真空下で濃縮し、３．５ｇ（７９％）の表題化合物を淡褐色固体として得た。 LC-MS (ES, m / z): 506
Step 2. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide

A solution of the product (6 g, 11.86 mmol) from the previous step in MeOH (60 mL) was stirred under H2 at Pd / C (600 mg) for 1 hour. The solid was removed by filtration and the filtrate was concentrated under vacuum to give 3.5 g (79%) of the title compound as a light brown solid.

トルエン（５ｍＬ）中の前ステップからの生成物（２００ｍｇ、０．５４ｍｍｏｌ）、１－ブロモ－４－フルオロベンゼン（９４ｍｇ、０．５４ｍｍｏｌ）、ＮａＯｔＢｕ（１５６ｍｇ）、ＲｕＰｈｏｓ（２．５ｍｇ）、および３Ｇ ＲｕＰｈｏｘ Ｐｄ触媒（４．５ｍｇ）の溶液を、８０℃で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１３０ｍｇ（５２％）の表題化合物を淡黄色の固体として得た。 LC-MS (ES, m / z): 372
Step 3. Synthesis of

Products from the previous step in toluene (5 mL) (200 mg, 0.54 mmol), 1-bromo-4-fluorobenzene (94 mg, 0.54 mmol), NaOtBu (156 mg), RuPhos (2.5 mg), and 3G. A solution of RuPhox Pd catalyst (4.5 mg) was stirred at 80 ° C. for 16 hours and then extracted with 2 x 30 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 130 mg (52%) of the title compound as a pale yellow solid.

ＴＨＦ（３ｍＬ）中の前のステップからの生成物（１３０ｍｇ、０．２７ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（３ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大５５．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、６２．４ｍｇ（６３％）の表題化合物をオフホワイトの固体として得た。 LC-MS (ES, m / z): 466
Step 4.1 Synthesis of 1- (4-fluorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

A 2N HCl aqueous solution (3 mL) was added dropwise to a solution of the product (130 mg, 0.27 mmol) from the previous step in THF (3 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (100 mg), instrument "A"; column "D"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 55.0% 20.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 62.4 mg (63%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 352
^{1 1} H NMR (300 Mhz, methanol-d ₄ ) δ 7.83 (dd, J = 3.0, 0.7 Hz, 1H), 7.22 (dd, J = 8.8, 3.0 Hz, 1H) ), 7.08 (dd, J = 8.8, 0.7Hz, 1H), 7.04 to 6.89 (m, 4H), 3.67 (d, J = 12.4Hz, 2H), 3.46 (m, 1H), 2.69 (m, 2H), 2.22 (d, J = 12.6 Hz, 2H), 2.09 to 1.87 (m, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－（５－クロロピリジン－２－イル）ピペリジン－４－スルホンアミドの合成

ＤＭＳＯ（５ｍＬ）中のＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－４－スルホンアミド（２００ｍｇ、０．５４ｍｍｏｌ）、ＤＩＥＡ（１３９ｍｇ、１．０８ｍｍｏｌ）、および５－クロロ－２－フルオロピリジン（１４２ｍｇ、１．０８ｍｍｏｌ）の溶液を、８０℃で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１７０ｍｇ（６５％）の表題化合物を淡黄色の固体として得た。 Example 67
1- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- (5-chloropyridine-2-yl) piperidine-4-sulfonamide

N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide (200 mg, 0.54 mmol), DIEA (139 mg, 1.08 mmol) in DMSO (5 mL), And a solution of 5-chloro-2-fluoropyridine (142 mg, 1.08 mmol) was stirred at 80 ° C. for 16 hours and then extracted with 2 x 30 mL of EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 170 mg (65%) of the title compound as a pale yellow solid.

３Ｎ ＨＣｌ水溶液（３ｍＬ）およびＴＨＦ（３ｍＬ）中の前のステップからの生成物（１７０ｍｇ、０．３５ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１７０ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で最大６２．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７８．３ｍｇ（６０％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 5- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

A solution of the product (170 mg, 0.35 mmol) from the previous step in 3N HCl aqueous solution (3 mL) and THF (3 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (170 mg), instrument "A"; column "D"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 62.0% 20.0% ACN in 7 minutes); detector. Purified by preparative-HPLC under UV254 / 220 nm conditions to give 78.3 mg (60%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 318
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 9.89 (br, 2H), 8.10 (d, J = 2.8Hz, 1H), 7.83 (d, J = 3.0Hz, 1H) , 7.58 (dd, J = 9.2, 2.8Hz, 1H), 7.19 (dd, J = 8.8, 3.0Hz, 1H), 6.93 (m, 2H), 4. 35 (d, J = 13.2Hz, 2H), 3.68 (tt, J = 12.3, 3.7Hz, 1H), 2.88 (t, J = 12.6Hz, 2H), 2.11. ~ 1.96 (m, 2H), 1.60 (qd, J = 12.6, 3.9 Hz, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－（４－クロロフェニル）ピペリジン－４－スルホンアミドの合成

トルエン（５ｍＬ）中のＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－４－スルホンアミド（２００ｍｇ、０．５４ｍｍｏｌ）、１－ブロモ－４－クロロベンゼン（２０５ｍｇ、１．０７ｍｍｏｌ）、ＮａＯｔＢｕ（１５６ｍｇ）、ＲｕＰｈｏｓ（２．５ｍｇ）、および３Ｇ ＲｕＰｈｏｘ Ｐｄ触媒（４．５ｍｇ）の溶液を、油浴中で、８０℃で１６時間攪拌した。得られた溶液を、２×３０ｍＬのＥｔＯＡｃで抽出し、混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１８０ｍｇ（６９％）の表題化合物を淡黄色固体として得た。 Example 68
1- (4-chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- (4-chlorophenyl) piperidine-4-sulfonamide

N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide (200 mg, 0.54 mmol), 1-bromo-4-chlorobenzene (205 mg) in toluene (5 mL) , 1.07 mmol), NaOtBu (156 mg), RuPhos (2.5 mg), and 3G RuPhox Pd catalyst (4.5 mg) were stirred in an oil bath at 80 ° C. for 16 hours. The resulting solution was extracted with 2 x 30 mL EtOAc, the mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to 180 mg (69%). The title compound was obtained as a pale yellow solid.

２Ｎ ＨＣｌ水溶液（３ｍＬ）およびＴＨＦ（３ｍＬ）中の前のステップからの生成物（１８０ｍｇ、０．３７ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１８０ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（７分間で２５．０％ＡＣＮを保持）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、９８ｍｇ（７１％）の表題化合物をオフホワイトの固体として得た。 LC-MS (ES, m / z): 482
Step 2.1-Synthesis of 4-chlorophenyl-N- (5-hydroxypyridin-2-yl) piperidine-4-sulfonamide

A solution of the product (180 mg, 0.37 mmol) from the previous step in 2N HCl aqueous solution (3 mL) and THF (3 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (180 mg), instrument "A"; column "D"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (holding 25.0% ACN in 7 minutes); detector, UV254 / 220 nm. Purification by preparative-HPLC to give 98 mg (71%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 368
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) 5 9.88 (br, 2H), 7.84 (d, J = 2.9 Hz, 1H), 7.28-7.14 (m, 3H), 7 0.02 to 6.88 (m, 3H), 3.80 (m, 2H), 3.57 (m, 1H), 2.73 (m, 2H), 2.11 to 1.96 (m, 2H) ), 1.73 (m, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－［４－（トリフルオロメチル）フェニル］ピペリジン－４－スルホンアミドの合成

Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］ピペリジン－４－スルホンアミド（２００ｍｇ、０．５４ｍｍｏｌ）、１－ブロモ－４－（トリフルオロメチル）ベンゼン（２１５ｍｇ、０．９６ｍｍｏｌ）、ＮａＯｔＢｕ（１５６ｍｇ）、ＲｕＰｈｏｓ（２．５ｍｇ）、３Ｇ ＲｕＰｈｏｘ Ｐｄ触媒（４．５ｍｇ）、およびトルエン（５ｍＬ）の溶液を、８０℃で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルクロマトグラフィーで精製し、１１５ｍｇ（４１％）の表題化合物を淡黄色の固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：５１６ Example 69
N- (5-Hydroxypyridin-2-yl) -1- [4- (trifluoromethyl) phenyl] piperidine-4-sulfonamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1- [4- (trifluoromethyl) phenyl] piperidine-4-sulfonamide

N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] piperidine-4-sulfonamide (200 mg, 0.54 mmol), 1-bromo-4- (trifluoromethyl) benzene (215 mg,) A solution of 0.96 mmol), NaOtBu (156 mg), RuPhos (2.5 mg), 3G RuPhox Pd catalyst (4.5 mg), and toluene (5 mL) was stirred at 80 ° C. for 16 hours and then in 2 x 30 mL. Extracted with EtOAc. The mixed organic layer was concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1/2) to give 115 mg (41%) of the title compound as a pale yellow solid. LC-MS: (ES, m / z): 516

ＴＨＦ（３ｍＬ）中の前のステップからの生成物（１１５ｍｇ、０．２２ｍｍｏｌ）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（３ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１１５ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（７分間で最大７５．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５６．５ｍｇ（６３％）の表題化合物をオフホワイトの固体として得た。 Step 2. Synthesis of N- (5-hydroxypyridin-2-yl) -1- [4- (trifluoromethyl) phenyl] piperidine-4-sulfonamide

A 2N HCl aqueous solution (3 mL) was added dropwise to a solution of the product (115 mg, 0.22 mmol) from the previous step in THF (3 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (115 mg), instrument "A"; column "D"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 75.0% 25.0% ACN in 7 minutes); Purification by preparative-HPLC under conditions of detector, UV254 / 220 nm gave 56.5 mg (63%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 402
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.86 (br, 2H), 7.84 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H) ), 7.20 (dd, J = 8.8, 3.0Hz, 1H), 7.02 (m, 3H), 3.99 (m, 2H), 3.66m, 1H), 2.88m, 2H), 2.11 to 1.98 (m, 2H), 1.70 (m, 2H).

ステップ１．６－メチルヘプタン－１－チオールの合成

ＥｔＯＨ（９ｍＬ）中の１－ブロモ－６－メチルヘプタン（９００ｍｇ、４．６６ｍｍｏｌ）の溶液に、１６時間にわたりＣＨ_４Ｎ_２Ｓ（３７２ｍｇ、４．８９ｍｍｏｌ）を加えた。次に、ＮａＯＨ水溶液（９ｍＬ）を、２時間にわたり加えた。得られた溶液を、２×２０ｍＬの石油エーテルで抽出し、混合物有機層を真空下で濃縮し、６８０ｍｇ（１００％）の表題化合物を無色の油として得た。 Example 70
N- (5-Hydroxypyridin-2-yl) -6-methylheptane-1-sulfonamide

Step 1.6-Synthesis of Methylheptane-1-thiol

CH _4N 2S (372 mg, 4.89 mmol) was added to a solution of 1-bromo-6 _- methylheptane (900 mg, 4.66 mmol) in EtOH (9 mL) over 16 hours. Next, an aqueous NaOH solution (9 mL) was added over 2 hours. The resulting solution was extracted with 2 x 20 mL petroleum ether and the organic layer of the mixture was concentrated under vacuum to give 680 mg (100%) of the title compound as a colorless oil.

ＣＨ_３ＣＮ（１０ｍＬ）中の前のステップからの生成物（６８０ｍｇ、４．６５ｍｍｏｌ）、Ｈ_２Ｏ_２（１．４ｍＬ）、およびＴｉＣｌ_４（４．６５ｍ Ｌ）の溶液を、室温で４時間攪拌し、次いで、３×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空下で濃縮し、５００ｍｇ（５１％）の表題化合物を黄色の油として得た。 Step 2.6 Synthesis of 3-methylheptane-1-sulfonyl chloride

A solution of the product (680 mg, 4.65 mmol), H ₂ O ₂ (1.4 mL), and TiCl ₄ (4.65 mL) from the previous step in CH ₃ CN (10 mL) at room temperature for 4 hours. It was stirred and then extracted with 3 x 20 mL EtOAc. The mixed organic layer was concentrated under vacuum to give 500 mg (51%) of the title compound as a yellow oil.

ピリジン（５ｍＬ）中の５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（５２８ｍｇ、２．３５ｍｍｏｌ）、および前のステップからの生成物（５００ｇ、２．３５ｍｍｏｌ）の溶液を、室温で１６時間攪拌し、次いで真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：５）を使用したシリカゲルカラムクロマトグラフィーで精製し、２６０ｍｇの表題化合物を黄色の固体として得た。 Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -6-methylheptane-1-sulfonamide

A solution of 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (528 mg, 2.35 mmol) in pyridine (5 mL) and the product from the previous step (500 g, 2.35 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated under vacuum and purified by silica gel column chromatography using EtOAc / Hexanes (1: 5) to give 260 mg of the title compound as a yellow solid.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（４ｍＬ）中の前のステップからの生成物（２６０ｍｇ、０．６５ｍｍｏｌ）の溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（２６０ｍｇ）を、
機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ４ＨＣＯ３）、およびＡＣＮ（７分間で最大５０．０％の２０．０％ＡＣＮ）；検出器、ｕｖ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８２．９ｍｇ（４５％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 401
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -6-methylheptane-1-sulfonamide

A solution of the product (260 mg, 0.65 mmol) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (260 mg),
Instrument "A"; Column "A"; Mobile phase, water (10 mM NH4HCO3), and ACN (up to 50.0% 20.0% ACN in 7 minutes); detector, uv254 / 220 nm. Purification by taking-HPLC gave 82.9 mg (45%) of the title compound as an off-white solid.

LCMS: (ES, m / z): 287
^{1 1} H NMR (300Mhz, methanol-d ₄ ) δ 7.84 (d, J = 3.0Hz, 1H), 7.20 (dd, J = 8.8, 3.0Hz, 1H), 6.99 ( d, J = 8.8Hz, 1H) 3.31 (m, 2H), 1.80 (m, 2H), 1.51 (m, 1H), 1.45 to 1.23 (m, 4H) , 1.17 (dd, J = 8.4, 5.9 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H).

ステップ１．４－（４－クロロフェニル）ピペリジン－１－スルホニルクロリドの合成

ＡＣＮ（５ｍＬ）中の４－（４－クロロフェニル）ピペリジン（５００ｍｇ、２．５６ｍｍｏｌ）の溶液に、ＳＯ_２Ｃｌ_２（２．０６ｇ）を０℃で滴下した。得られた溶液を、室温で１６時間攪拌し、次いで真空下で濃縮し、５００ｍｇ（６７％）の表題化合物をオフホワイト固体として得た。 Example 71
4- (4-Chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperidine-1-sulfonamide

Step 1.4-Synthesis of 4- (4-chlorophenyl) piperidine-1-sulfonyl chloride

SO ₂ Cl ₂ (2.06 g) was added dropwise at 0 ° C. to a solution of 4- (4-chlorophenyl) piperidine (500 mg, 2.56 mmol) in ACN (5 mL). The resulting solution was stirred at room temperature for 16 hours and then concentrated under vacuum to give 500 mg (67%) of the title compound as an off-white solid.

ピリジン（５ｍＬ）中の前のステップからの生成物（２４４ｍｇ、１．０９ｍｍｏｌ）の溶液に、４－（４－クロロフェニル）ピペリジン－１－スルホニルクロリド（５００ｍｇ、１．７０ｍｍｏｌ）を０℃で攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌し、次いで真空下で濃縮し、ＥｔＯＡｃ／ヘキサン（１：１）を使用したシリカゲルクロマトグラフィーで精製し、８０ｍｇ（１５％）の表題化合物をオフホワイト固体として得た。 Step 2. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-chlorophenyl) piperidine-1-sulfonamide

To a solution of the product (244 mg, 1.09 mmol) from the previous step in pyridine (5 mL) is stirred 4- (4-chlorophenyl) piperidine-1-sulfonyl chloride (500 mg, 1.70 mmol) at 0 ° C. While dripping. The resulting solution was stirred at room temperature for 2 hours, then concentrated under vacuum and purified by silica gel chromatography using EtOAc / Hexanes (1: 1) to give 80 mg (15%) of the title compound as an off-white solid. Got as.

２Ｎ ＨＣｌ水溶液（１ｍＬ）およびＴＨＦ（２ｍＬ）中の前のステップからの生成物（８０ｍｇ、０．１７ｍｍｏｌ）の溶液を、
室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（８０ｍｇ）を、機器「Ｂ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大６５．０％の３３．０％ＡＣＮ）の条件で、分取－ＨＰＬＣで精製し、１８．８ｍｇ（３１％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 482
Step 3.4-Synthesis of 4-chlorophenyl-N- (5-hydroxypyridin-2-yl) piperidine-1-sulfonamide

A solution of the product (80 mg, 0.17 mmol) from the previous step in 2N HCl aqueous solution (1 mL) and THF (2 mL),
The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (80 mg) under the conditions of instrument "B"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 65.0% 33.0% ACN in 7 minutes). Purification by preparative-HPLC gave 18.8 mg (31%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 368
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 10.33-9.38 (m, 2H), 7.84 (d, J = 2.9Hz, 1H), 7.39-7.31 (m, 2H), 7.25 to 7.18 (m, 3H), 7.06 (d, J = 8.8Hz, 1H), 3.81 to 3.63 (m, 2H), 2.80 (m, 2H), 2.60 (m, 1H), 1.86 to 1.67 (m, 2H), 1.48 (m, 2H).

ステップ１．Ｎ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－２－オキソオキサゾリジン－３－スルホンアミドの合成

ＤＣＭ（１５ｍＬ）中のクロロスルホニルイソシアネート（２８２ｍｇ、２ｍｍｏｌ）の溶液に、２－ブロモエタノール（２４８ｍｇ、２ｍｍｏｌ）を０℃で滴下した。混合物を、０．５時間攪拌し、次いで、ＤＣＭ（１５ｍＬ）中の５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－アミン（４４８ｍｇ、２ｍｍｏｌ）、およびＥｔ_３Ｎ（６００ｍｇ、６ ｍｍｏｌ）の溶液を、０℃で滴下した。得られた溶液を。室温で２時間攪拌し、次いで真空下で濃縮し、ＥｔＯＡｃ／ＭｅＯＨ （１５／１）を使用したシリカゲルクロマトグラフィーで精製し、表題化合物を淡黄色固体として得た（５００ｍｇ、６７％）。 Scheme X
Example 72
N- (5-Hydroxypyridin-2-yl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide

Step 1. Synthesis of N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -2-oxooxazolidine-3-sulfonamide

2-Bromoethanol (248 mg, 2 mmol) was added dropwise at 0 ° C. to a solution of chlorosulfonyl isocyanate (282 mg, 2 mmol) in DCM (15 mL). The mixture is stirred for 0.5 hours, then 5- (tert-butyldimethylsilyloxy) pyridin- ₂ -amine (448 mg, 2 mmol) in DCM (15 mL), and Et 3N (600 mg, 6 mmol). The solution was added dropwise at 0 ° C. The resulting solution. The mixture was stirred at room temperature for 2 hours, then concentrated under vacuum and purified by silica gel chromatography using EtOAc / MeOH (15/1) to give the title compound as a pale yellow solid (500 mg, 67%).

ＭｅＣＮ（１．５ｍＬ）中の前のステップからの生成物（１１５ｍｇ、０．３ｍｍｏｌ）、１－（４－フルオロフェニル）ピペラジン（１０８ｍｇ、０．６ｍｍｏｌ）、およびＤＩＰＥＡ（０．６ｍＬ）の溶液を、マイクロ波加熱を使用して０．５時間１３０℃に加熱した。次いで、混合物を室温に冷却し、真空下で濃縮し、Ｃ Ｈ_２Ｃｌ_２／ＥｔＯＡｃ（１０／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、７０ｍｇ（５０％）の表題化合物を淡黄色固体として得た。 LC-MS: (ES, m / z): 374.2
Step 2. Synthesis of N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -4- (4-fluorophenyl) piperazine-1-sulfonamide

A solution of the product (115 mg, 0.3 mmol), 1- (4-fluorophenyl) piperazine (108 mg, 0.6 mmol), and DIPEA (0.6 mL) from the previous step in MeCN (1.5 mL). , Heated to 130 ° C. for 0.5 hours using microwave heating. The mixture was then cooled to room temperature, concentrated under vacuum and purified by silica gel column chromatography using CH ₂ Cl ₂ / EtOAc (10/1) to give 70 mg (50%) of the title compound pale yellow. Obtained as a solid.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（７０ｍｇ、０．１５ｍｍｏｌ）の溶液に、濃縮ＨＣｌ（１ｍＬ）を０℃で加えた。得られた溶液を、室温で２時間攪拌し、次いで真空下で濃縮した。残留物を、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４９．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１７．９ｍｇ（２４％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 467.1
Step 3. Synthesis of N- (5-hydroxypyridin-2-yl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide

Concentrated HCl (1 mL) was added at 0 ° C. to a solution of product (70 mg, 0.15 mmol) from the previous step in THF (2 mL). The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Residues, instrument "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 49.0% 20.0% ACN in 8 minutes); detector, UV254 / 220 nm. Purification by preparative-HPLC to give 17.9 mg (24%) of the title compound as a white solid.

LC-MS: (ES, m / z): 353.1
^{1 1} H NMR (400 Mhz, DMSO-d ₆ ) δ 9.74 (s, 2H), 7.80 (d, J = 2.9 Hz, 1H), 7.19 (dd, J = 8.8, 3) .0Hz, 1H), 7.09 to 7.00 (m, 3H), 6.97 to 6.90 (m, 2H), 3.27 to 3.18 (m, 4H), 3.11 to 3 .02 (m, 4H).

ステップ１．Ｎ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－４－（５－クロロピリジン－２－イル）ピペラジン－１－スルホンアミドの合成

ＭｅＣＮ（１．５ｍＬ）中のＮ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－２－オキソオキサゾリジン－３－スルホンアミド（１６５ｍｇ、０．４５ｍｍｏｌ）、１－（５－クロロピリジン－２－イル）ピペラジン（１８０ｍｇ、０．９ｍｍｏｌ）、およびＤＩＰＥＡ（０．６ｍＬ）の溶液を、マイクロ波加熱を使用して０．５時間１３０℃に加熱した。次いで、混合物を室温に冷却し、真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＥｔＯＡｃ（１０／１）を使用してシリカゲルクロマトグラフィーで精製し、１５０ ｍｇ（７２％）の表題化合物を淡黄色の泡として得た。 Example 73
4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-sulfonamide

Step 1. Synthesis of N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -4- (5-chloropyridine-2-yl) piperazine-1-sulfonamide

N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -2-oxooxazolidine-3-sulfonamide (165 mg, 0.45 mmol), 1- (5- (5-) in MeCN (1.5 mL) A solution of chloropyridin-2-yl) piperazine (180 mg, 0.9 mmol) and DIPEA (0.6 mL) was heated to 130 ° C. for 0.5 hours using microwave heating. The mixture was then cooled to room temperature, concentrated under vacuum and purified by silica gel chromatography using CH ₂ Cl ₂ / EtOAc (10/1) to give 150 mg (72%) of the title compound in pale yellow. Obtained as foam.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３ｍｍｏｌ）の溶液に、濃縮ＨＣｌ （１ｍＬ）を０℃で加えた。得られた溶液を室温で２時間攪拌し、次いで、真空下で濃縮し、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４９．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、８２．１ｍｇ（７２％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 484.3
Step 2.4 Synthesis of 4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-sulfonamide

To a solution of product (150 mg, 0.3 mmol) from the previous step in THF (2 mL) was added concentrated HCl (1 mL) at 0 ° C. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum to device "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 49. in 8 minutes. 0% 20.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 82.1 mg (72%) title compound as a white solid.

LC-MS: (ES, m / z): 370.1
^{1 1} H NMR (400Mhz, DMSO-d ₆ ) δ 9.91 (br, 2H), 8.11 (d, J = 2.7Hz, 1H), 7.76 (d, J = 2.9Hz, 1H) , 7.62 (dd, J = 9.1, 2.7 Hz, 1H), 7.17 (dd, J = 8.8, 2.9 Hz, 1H), 7.03 (d, J = 8) .8Hz, 1H), 6.88 (d, J = 9.1Hz, 1H), 3.49 (m, 4H), 3.18 (m, 4H).

ステップ１．Ｎ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－４－（４－クロロフェニル）ピペラジン－１－スルホンアミドの合成

ＭｅＣＮ（１．５ｍＬ）中のＮ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－２－オキソオキサゾリジン－３－スルホンアミド（１６５ｍｇ、０．４５ｍｍｏｌ）、１－（４－クロロフェニル）ピペラジン（１８０ｍｇ、０．９ｍｍｏｌ）、およびＤＩＰＥＡ（０．６ｍＬ）の溶液を、マイクロ波加熱を使用して０．５時間１３０℃に加熱し、次いで、室温に冷却し、真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＥｔＯＡｃ（１０／１）を使用してシリカゲルクロマトグラフィーで精製し、１５０ｍｇ（７２％）の表題化合物を淡黄色の泡として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４８３．２ Example 74
4- (4-Chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-sulfonamide

Step 1. Synthesis of N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -4- (4-chlorophenyl) piperazine-1-sulfonamide

N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -2-oxooxazolidine-3-sulfonamide (165 mg, 0.45 mmol), 1- (4- (4-) in MeCN (1.5 mL) A solution of chlorophenyl) piperazine (180 mg, 0.9 mmol) and DIPEA (0.6 mL) was heated to 130 ° C. for 0.5 hours using microwave heating, then cooled to room temperature and concentrated under vacuum. Then, purification was performed by silica gel chromatography using CH ₂ Cl ₂ / EtOAc (10/1) to obtain 150 mg (72%) of the title compound as a pale yellow foam. LC-MS: (ES, m / z): 483.2

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．３ｍｍｏｌ）の溶液に、濃縮ＨＣｌ（１ｍＬ）を０℃で加えた。得られた溶液を室温で２時間攪拌し、次いで、真空下で濃縮し、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大４９．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７７．５ｍｇ（６８％）の表題化合物を白色固体として得た。 Step 2.4 Synthesis of 4- (4-chlorophenyl) -N- (5-hydroxypyridin-2-yl) piperazine-1-sulfonamide

To a solution of product (150 mg, 0.3 mmol) from the previous step in THF (2 mL) was added concentrated HCl (1 mL) at 0 ° C. The resulting solution is stirred at room temperature for 2 hours and then concentrated under vacuum with equipment "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (maximum in 8 minutes). 49.0% 20.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 77.5 mg (68%) of the title compound as a white solid.

LC-MS: (ES, m / z): 369.1
^{1 1} H NMR (400 Mhz, DMSO-d ₆ ) δ 10.18 (s, 1H), 9.72 (s, 1H), 7.80 (d, J = 3.0Hz, 1H), 7.26-7 .21 (m, 2H), 7.19 (dd, J = 8.8, 3.0Hz, 1H), 7.05 (d, J = 8.8Hz, 1H), 6.97-6.91 ( m, 2H), 3.26 to 3.19 (m, 4H), 3.15 to 3.07 (m, 4H).

ステップ１．Ｎ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－４－（４－（トリフルオロメチル）フェニル）ピペラジン－１－スルホンアミドの合成

ＭｅＣＮ（１．５ｍＬ）中のＮ－（５－（ｔｅｒｔ－ブチルジメチルシリルオキシ）ピリジン－２－イル）－２－オキソオキサゾリジン－３－スルホンアミド（１６５ｍｇ、０．４５ｍｍｏｌ）、１－（４－（トリフルオロメチル）フェニル）ピペラジン（２０５ ｍｇ、０．９ｍｍｏｌ）、およびＤＩＰＥＡ（０．６ｍＬ）の溶液を、マイクロ波加熱を使用して０．５時間１３０℃に加熱し、次いで、室温に冷却し、真空下で濃縮し、ＣＨ_２Ｃｌ_２／ＥｔＯＡｃ（１０／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１５０ｍｇ（６８％）の表題化合物を淡黄色の泡として得た。 Example 75
N- (5-Hydroxypyridin-2-yl) -4- (4- (trifluoromethyl) phenyl) -piperazin-1-sulfonamide

Step 1. Synthesis of N- (5- (tert-butyldimethylsilyloxy) pyridin-2-yl) -4- (4- (trifluoromethyl) phenyl) piperazin-1-sulfonamide

N- (5- (tert-butyldimethylsilyloxy) pyridine-2-yl) -2-oxooxazolidine-3-sulfonamide (165 mg, 0.45 mmol), 1- (4- (4-) in MeCN (1.5 mL) A solution of (trifluoromethyl) phenyl) piperazine (205 mg, 0.9 mmol) and DIPEA (0.6 mL) was heated to 130 ° C. for 0.5 hours using microwave heating and then cooled to room temperature. Then concentrated under vacuum and purified by silica gel column chromatography using CH ₂ Cl ₂ / EtOAc (10/1) to give 150 mg (68%) of the title compound as pale yellow foam.

ＴＨＦ（２ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．２９ｍｍｏｌ）の溶液に、濃縮ＨＣｌ（１ｍＬ）を０で加えた。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮し、機器「Ａ」；カラム「Ａ」；移動相、１ ０ｍＭ ＮＨ_４ＨＣＯ_３水溶液、およびＡＣＮ（８分間で最大４９．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、７１．８ｍｇ（６１％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 517.3
Step 2. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (4- (trifluoromethyl) phenyl) piperazin-1-sulfonamide

Concentrated HCl (1 mL) was added at 0 to a solution of the product (150 mg, 0.29 mmol) from the previous step in THF (2 mL). The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum to device "A"; column "A"; mobile phase, 10 mM NH ₄ HCO ₃ aqueous solution, and ACN (up to 49 in 8 minutes). 0.0% 20.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 71.8 mg (61%) of the title compound as a white solid.

LC-MS: (ES, m / z): 403.2
^{1 1} H NMR (400Mhz, DMSO-d ₆ ) δ 10.18 (s, 1H), 9.73 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.51 ( d, J = 8.7 Hz, 2H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 7.08 to 7.04 (m, 3H), 3.31 to 3 .26 (m, 4H), 3.26 to 3.21 (m, 4H).

ステップ１．３－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－１－［（４－クロロフェニル）メチル］尿素の合成

４０ｍＬバイアル内の、ＣＨ_２Ｃｌ_２（５ｍＬ）中の１－（４－クロロフェニル）メタンアミン（２４ｍｇ、０．１７ｍｍｏｌ、１．２０当量）、ＴＥＡ（４２ｍｇ、０．４２ｍｍｏｌ、３．００当量）、および４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（５０ｍｇ、０．１４ｍｍｏｌ、１．００当量）の溶液を、室温で１６時間攪拌した。次いで、混合物を、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、混合有機層を、Ｎａ_２ＳＯ_４で乾燥させ、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／２）を使用して分取ＴＬＣにより精製し、５０ｍｇ（９２％）の表題化合物をオフホワイト固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：３９２ Example 76
1-[(4-chlorophenyl) methyl] -3- (5-hydroxypyridin-2-yl) urea

Step 1.3- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -1-[(4-chlorophenyl) methyl] urea synthesis

1- (4-chlorophenyl) methaneamine in CH ₂ Cl ₂ (5 mL) (24 mg, 0.17 mmol, 1.20 eq), TEA (42 mg, 0.42 mmol, 3.00 eq), and in a 40 mL vial. A solution of 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridin-2-ylcarbamate (50 mg, 0.14 mmol, 1.00 eq) was stirred at room temperature for 16 hours. The mixture was then extracted with 2 x 20 mL CH ₂ Cl ₂ and the mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc / Hexanes (1/2) to give 50 mg (92%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 392

１００ｍＬ丸底フラスコ内の、ＴＨＦ（４ｍＬ）中の前のステップからの生成物（５０ｍｇ、０．１３ｍｍｏｌ、１．００当量）の溶液を、２ＭのＨＣｌ水溶液（２ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌し、次いで真空内で濃縮した。粗生成物（５０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大５４．０％の２５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、３２ｍｇ（９０％）の表題化合物をオフホワイトの固体として得た。 Step 2.1-Synthesis of 3-[(4-chlorophenyl) methyl] -3- (5-hydroxypyridin-2-yl) urea

A solution of the product (50 mg, 0.13 mmol, 1.00 eq) from the previous step in THF (4 mL) in a 100 mL round bottom flask was added dropwise with stirring 2 M aqueous HCl solution (2 mL). The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (50 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 54.0% 25.0% ACN in 8 minutes); The detector was purified by preparative-HPLC under UV 254/220 nm conditions to give 32 mg (90%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 277.8
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.96 (s, 1H), 8.35 (s, 1H), 7.71 (dd, J = 2.8) , 0.7Hz, 1H), 7.44 to 7.07 (m, 6H), 4.34 (d, J = 6.0Hz, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－［（３，４－ジフルオロフェニル）メチル］ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の４－フルオロフェニルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－カルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、Ｅｔ_３Ｎ（８４ｍｇ、３．００当量）、および１－［（３，４－ジフルオロフェニル）メチル］ピペラジン（５９ｍｇ、０．２８ｍｍｏｌ、１．００当量）の溶液を、室温で１６時間攪拌した。次いで、２×３０ｍＬのＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、９６ｍｇ（７５％）の表題化合物をオフホワイト固体として得た。 Example 77
4-[(3,4-difluorophenyl) methyl] -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4-[(3,4-difluorophenyl) methyl] piperazine-1-carboxamide

4-Fluorophenyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -carbamate (100 mg, 0.28 mmol, 1.00 eq) in CH ₂ Cl ₂ (5 mL), Et. A solution of 3N (84 mg, _3.00 eq) and 1-[(3,4-difluorophenyl) methyl] piperazine (59 mg, 0.28 mmol, 1.00 eq) was stirred at room temperature for 16 hours. It was then extracted with 2 x 30 mL EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 96 mg (75%) of the title compound as an off-white solid.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（９６ｍｇ、０．２１ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで真空内で濃縮した。粗生成物（９６ｍｇ）を、機器「Ａ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大１８．０％の１．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、３８．６ｍｇ（５３％）の表題化合物をオフホワイトの固体として得た。 Step 2.4 [Synthesis of (3,4-difluorophenyl) methyl] -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (96 mg, 0.21 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (96 mg), instrument "A"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 18.0% 1.0% ACN in 7 minutes); detector Purified by preparative-HPLC under UV254 / 220 nm conditions to give 38.6 mg (53%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 349
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 8.13 (s, 1H), 7.76 (d, J = 2.9Hz, 1H), 7.55 (d) , J = 8.9Hz, 1H), 7.43 to 7.27 (m, 2H), 7.17 to 7.10 (m, 2H), 3.53 to 3.43 (m, 6H), 2 .33 (m, 4H).

ステップ１．４－（４－フルオロピリジン－２－イル）ピペラジン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の２－ブロモ－４－フルオロピリジン（６００ｍｇ、３．４ｍｍｏｌ、１．００当量）、ベンジルピペラジン－１－カルボキシレート（７５４ｍｇ、３．４２ｍｍｏｌ、１．００当量）、ＣＳ_２ＣＯ_３（３．３ｇ、３．００当量）、Ｂｒｅｔｔｐｈｏｓ（１８ｍｇ、０．０１当量）、Ｂｒｅｔｔｐｈｏｓ Ｐｄ Ｇ３触媒（３１ｍｇ、０．０１当量）の混合物を、油浴中で、８０℃で１６時間、３０ｍＬの密閉管中で攪拌した。得られた混合物を冷却し、水で希釈し、２×３０ｍＬのＥｔＯＡｃで抽出した。有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１１０ｍｇ（１０％）の表題化合物をオフホワイト固体として得た。 Example 78
4- (4-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

Step 1.4-Synthesis of 4- (4-fluoropyridin-2-yl) piperazine-1-carboxylate

2-Bromo-4-fluoropyridine (600 mg, 3.4 mmol, 1.00 eq) in toluene (10 mL), benzylpiperazine-1-carboxylate (754 mg, 3.42 mmol, 1.00 eq), CS ₂ CO A mixture of ₃ (3.3 g, 3.00 eq), Bretphos (18 mg, 0.01 eq), and Brettophos Pd G3 catalyst (31 mg, 0.01 eq) in an oil bath at 80 ° C. for 16 hours, 30 mL. Stirred in a closed tube. The resulting mixture was cooled, diluted with water and extracted with 2 x 30 mL EtOAc. The organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 110 mg (10%) of the title compound as an off-white solid.

ＭｅＯＨ（５ｍＬ）中の前のステップからの生成物（１１０ｍｇ、０．３５ｍｍｏｌ、１．００当量）の溶液を、室温で、１００ｍＬ丸底フラスコ内でＰｄ／Ｃ（炭素で１０％、１１ｍｇ）で、Ｈ_２下で４時間攪拌した。固体を濾過により除去した。得られた溶液を真空内で濃縮し、６０ｍｇ（９５％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 316
Step 2.1-Synthesis of 4- (4-fluoropyridin-2-yl) piperazine

A solution of the product (110 mg, 0.35 mmol, 1.00 eq) from the previous step in MeOH (5 mL) at room temperature in a 100 mL round bottom flask at Pd / C (10% carbon, 11 mg). , H ₂ for 4 hours. The solid was removed by filtration. The resulting solution was concentrated in vacuo to give 60 mg (95%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（６０ｍｇ、０．３３ｍｍｏｌ、１．２０当量）、ＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）、および４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）－オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）の溶液を、室温で４０ ｍＬバイアル内で１６時間攪拌し、次いで、２×３０ｍＬのＥｔＯＡｃで抽出し、有機層を混合し、真空で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１００ｍｇ（８４％）の表題化合物をオフホワイト固体として得た。ＬＣ－ＭＳ：（ＥＳ、ｍ／ｚ）：４３２ LC-MS: (ES, m / z): 182
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (4-fluoropyridine-2-yl) piperazine-1-carboxamide

Products from the previous step in CH ₂ Cl ₂ (5 mL) (60 mg, 0.33 mmol, 1.20 eq), TEA (84 mg, 0.83 mmol, 3.00 eq), and 4-fluorophenyl N- A solution of 5-[(tert-butyldimethylsilyl) -oxy] pyridine-2-ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) was stirred in a 40 mL vial at room temperature for 16 hours, then 2 Extracted with x30 mL EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 100 mg (84%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 432

１００ｍＬ丸底フラスコ内の、ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．２３ｍｍｏｌ、１．００当量）の溶液を、２ＭのＨＣｌ（２ｍＬ）を攪拌しながら加えた。得られた溶液を、室温で２時間攪拌し、次いで真空内で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大３９．０％の１５．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２４．１ｍｇ（３３％）の表題化合物をオフホワイトの固体として得た。 Step 4.4 Synthesis of 4- (4-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (100 mg, 0.23 mmol, 1.00 eq) from the previous step in THF (4 mL) in a 100 mL round bottom flask was added with stirring 2M HCl (2 mL). The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (100 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 39.0% 15.0% ACN in 8 minutes); Purification by preparative-HPLC on detector, UV254 / 220 nm conditions gave 24.1 mg (33%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 318
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 9.42 (br, 1H), 8.89 (s, 1H), 8.10 (dd, J = 9.8, 5.7 Hz, 1H), 7.77 (d, J = 2.9 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 2.9 Hz, 1H) , 6.71 (dd, J = 13.2, 2.2 Hz, 1H), 6.53 (ddd, J = 8.1, 5.7, 2.1 Hz, 1H), 3.56-3 .53 (m, 8H).

ステップ１．Ｔｅｒｔ－ブチル４－（３，５，６－トリフルオロピリジン－２－イル）ピペラジン－１－カルボキシレートの合成

ＮＭＰ（１０ｍＬ）中の２，３，５，６－テトラフルオロピリジン（１．５ｇ、９．９３ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（１．０ｇ、５．３７ｍｍｏｌ、０．５４当量）、およびＤＩＰＥＡ（２ｍＬ）の溶液を、１５０°Ｃで４０ｍＬの密閉管内で一晩攪拌した。次いで、水を加えることによって反応物をクエンチした。得られた溶液を、ＥｔＯＡｃで抽出し、有機層を混合し、塩水で洗浄し、真空内で濃縮し、ＥｔＯＡｃ／石油エーテル（１：１０）を使用してシリカゲルカラムクロマトグラフィーで精製し、１．２ｇ（３８％）の表題化合物を白色固体として得た。 Example 79
4- (3,5-Difluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-carboxamide

Step 1. Synthesis of tert-butyl 4- (3,5,6-trifluoropyridine-2-yl) piperazine-1-carboxylate

2,3,5,6-tetrafluoropyridine (1.5 g, 9.93 mmol, 1.00 eq), tert-butylpiperazin-1-carboxylate (1.0 g, 5.37 mmol) in NMP (10 mL), A solution of 0.54 eq) and DIPEA (2 mL) was stirred at 150 ° C. in a 40 mL closed tube overnight. The reaction was then quenched by the addition of water. The resulting solution is extracted with EtOAc, the organic layer is mixed, washed with salt water, concentrated in vacuo and purified by silica gel column chromatography using EtOAc / petroleum ether (1:10), 1 .2 g (38%) of the title compound was obtained as a white solid.

LC-MS: (ES, m / z): 218.0
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 to 8.08 (m, 1H), 3.44 (t, J = 5.0 Hz, 4H), 3.35-3.28 (t, J = 5.0Hz, 4H), 1.42 (s, 9H).

トルエン（２．２ｍＬ）中の前のステップからの生成物（１．２ｇ、３．７８ｍｍｏｌ、１．００当量）、Ｃｐ_２ＴｉＣｌ_２（１００ｍｇ、０．４０ｍｍｏｌ、０．１１当量）、およびＲＥＤ－ＡＬ（登録商標）の溶液を、室温で一晩攪拌し、次いで、水を加えることによりクエンチした。得られた溶液をＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／石油エーテル（１０：１）を使用してシリカゲルカラムクロマトグラフィーで精製し、８００ｍｇの表題化合物を黄色固体として得た。 Step 2. Synthesis of tert-butyl 4- (3,5-difluoropyridin-2-yl) piperazine-1-carboxylate

Products from the previous step in toluene (2.2 mL) (1.2 g, 3.78 mmol, 1.00 eq), Cp ₂ TiCl ₂ (100 mg, 0.40 mmol, 0.11 eq), and RED-. The solution of AL® was stirred at room temperature overnight and then quenched by the addition of water. The resulting solution was extracted with EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (10: 1) to give 800 mg of the title compound as a yellow solid.

４Ｎ ＨＣｌ／ジオキサン（１０ｍＬ）中の前のステップからの生成物（粗製、８００ｍｇ、２．６７ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空内で濃縮した。溶液のｐＨ値を、ＮａＨＣＯ _３溶液でｐＨ８～９に調整した。得られた溶液を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合した。溶媒を除去して、３００ｍｇの表題化合物を黄色の油として得た。 LC-MS: (ES, m / z): 200.3
Step 3.1-Synthesis of 3- (3,5-difluoropyridin-2-yl) piperazine

A solution of the product (crude, 800 mg, 2.67 mmol, 1.00 eq) from the previous step in 4N HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to pH 8-9 with a NaHCO ₃ solution. The resulting solution was extracted with CH ₂ Cl ₂ and mixed with an organic layer. The solvent was removed to give 300 mg of the title compound as a yellow oil.

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップからの生成物（１５０ｍｇ、０．７５ｍｍｏｌ、１．８２当量）、４－フルオロフェニルＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］カルバメート（１５０ｍｇ、０．４１ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（３００ｍｇ、２．９７ｍｍｏｌ、７．１８当量）の溶液を、室温で一晩攪拌した。次いで、反応物を、水を加えることによりクエンチした。得られた溶液を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／石油エーテル（１：６）を使用してシリカゲルカラムクロマトグラフィーで精製し、８０ｍｇ（４３％）の表題化合物を黄色固体として得た。 LC-MS: (ES, m / z): 200.0
Step 4. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3,5-difluoropyridine-2-yl) piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (10 mL) (150 mg, 0.75 mmol, 1.82 eq), 4-fluorophenyl N- [5-[(tert-butyldimethylsilyl) oxy] pyridine- A solution of ₂ -yl] carbamate (150 mg, 0.41 mmol, 1.00 eq) and Et 3N (300 mg, 2.97 mmol, 7.18 eq) was stirred overnight at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with CH ₂ Cl ₂ , mixed with an organic layer and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1: 6) to give 80 mg (43%) of the title compound as a yellow solid.

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（５ｍＬ）中の前のステップからの生成物（８０ｍｇ、０．１８ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌し、次いで、真空内で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３＋０．１％ＮＨ_３．Ｈ_２Ｏ）、およびＡＣＮ（８分間で最大６０．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２８．１ｍｇ（４７％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 450.1
Step 5. Synthesis of 4- (3,5-difluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

A solution of the product (80 mg, 0.18 mmol, 1.00 eq) from the previous step in 2N HCl aqueous solution (2 mL) and THF (5 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. .. Crude product (100 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O), and ACN (up to 60. in 8 minutes. 0% 30.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 28.1 mg (47%) of the title compound as a white solid.

LC-MS: (ES, m / z): 336.3
^{1 1} H NMR (400Mhz, DMSO-d ₆ ) δ 9.37 (br, 1H), 8.90 (s, 1H), 8.13 (d, J = 2.5Hz, 1H), 7.89-7 .77 (m, 2H), 7.60 (d, J = 8.9Hz, 1H), 7.14 (dd, J = 8.9, 3.0Hz, 1H), 3.63 to 3.55 (M, 4H) 3.35 to 3.27 (m, 4H).

ステップ１．ｔｅｒｔ－ブチル４－（１－フェニル－１Ｈ－ピラゾール－４－イル）ピペラジン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の４－ブロモ－ｌ－フェニル－１Ｈ－ピラゾール（５００ｍｇ、２．２４ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（４１９ｍｇ、２．２５ｍｍｏｌ、１．００当量）、ＮａＯｔＢｕ（３２４ｍｇ、１．５０当量）、ＤａｖｅＰｈｏｓ（４５ｍｇ、０．０５当量）、およびＰｄ_２（ｄｂａ_３（１０５ｍｇ、０．１１ｍｍｏｌ、０．０５当量）の溶液を、油浴中で、９０℃で１６時間、Ｎ_２下で、３０ｍＬの密封管内で攪拌した。得られた溶液を、２×３０ｍＬのＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／石油エーテル（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、６００ｍｇ（８２％）の表題化合物をオフホワイト固体として得た。 Example 80
N- (5-Hydroxypyridin-2-yl) -4- (1-phenyl-1H-pyrazole-4-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (1-phenyl-1H-pyrazole-4-yl) piperazine-1-carboxylate

4-bromo-l-phenyl-1H-pyrazole (500 mg, 2.24 mmol, 1.00 eq), tert-butylpiperazin-1-carboxylate (419 mg, 2.25 mmol, 1.00 eq) in toluene (10 mL) ), NaOtBu (324 mg, 1.50 eq), Dave Phos (45 mg, 0.05 eq), and Pd ₂ (dba ₃ (105 mg, 0.11 mmol, 0.05 eq)) in an oil bath, 90. Stirred in a 30 mL sealed tube under N ₂ for 16 hours at ° C. The resulting solution was extracted with 2 x 30 mL EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was enriched with EtOAc. Purification by silica gel column chromatography using / petroleum ether (1/1) gave 600 mg (82%) of the title compound as an off-white solid.

ジオキサン（６ｍＬ）中の前のステップからの生成物（６００ｍｇ、１．８３ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（３ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌した。溶液のｐＨ値を、ＮａＨＣＯ_３ （２Ｍ）で７に調整した。得られた溶液を、２×３０ ｍＬのＥｔＯＡｃで抽出し、混合有機層を混合し、真空内で濃縮し、１１０ｍｇ（２６％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 329.1
Step 2.1-Synthesis of piperazine (1-phenyl-1H-pyrazole-4-yl) piperazine

A 2N HCl aqueous solution (3 mL) was added dropwise to a solution of the product (600 mg, 1.83 mmol, 1.00 eq) from the previous step in dioxane (6 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to 7 with NaHCO ₃ (2M). The resulting solution was extracted with 2 x 30 mL EtOAc, mixed organic layers were mixed and concentrated in vacuo to give 110 mg (26%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．４４ｍｍｏｌ、１．５０当量）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）の溶液を、室温で１６時間攪拌した。得られた溶液を、２ｘ２０ｍＬのＣＨ_２Ｃｌ_２で抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１１０ｍｇ（８３％）の表題化合物をオフホワイト固体として得た。 LC-MS: (ES, m / z): 229.00
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (1-phenyl-1H-pyrazole-4-yl) piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (100 mg, 0.44 mmol, 1.50 eq), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridine-2 -A solution of ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) and TEA (84 mg, 0.83 mmol, 3.00 eq) was stirred at room temperature for 16 hours. The resulting solution was extracted with 2x20 mL CH ₂ Cl ₂ , mixed with an organic layer and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 110 mg (83%) of the title compound as an off-white solid.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１１０ｍｇ、０．２３ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら２ Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで真空内で濃縮した。粗生成物（１１０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大４９．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５８．３ｍｇ（７０％）の表題化合物をオフホワイトの固体として得た。 LC-MS (ES, m / z): 479.10
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (1-phenyl-1H-pyrazole-4-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (110 mg, 0.23 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (110 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 49.0% 20.0% ACN in 8 minutes); The detector was purified by preparative-HPLC under UV 254/220 nm conditions to give 58.3 mg (70%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 365.3
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.43 (br, 1H), 8.91 (s, 1H), 8.08 (s, 1H), 7.82-7.70 (m, 3H) ), 7.63 to 7.53 (m, 2H), 7.43 (t, J = 7.9Hz, 2H), 7.21 (t, J = 7.4Hz, 1H), 7.12 (dd) , J = 8.9, 3.0Hz, 1H), 3.58 (m, 4H), 2.95 (m, 4H).

ステップ１．ｔｅｒｔ－ブチル４－（１－メチル－１Ｈ－インダゾール－４－イル）ピペラジン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の４－ブロモ－１－メチル－１Ｈ－インダゾール（５００ｍｇ、２．３７ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（４４３ｍｇ、２．３８ｍｍｏｌ、１．００当量）、ＮａＯｔＢｕ（３４３ ｍｇ、１．５０当量）、ＤａｖｅＰｈｏｓ（９ｍｇ、０．０１当量）、およびＰｄ_２（ｄｂａ）_３（２２ｍｇ、０．０２ｍｍｏｌ、０．０１当量）の溶液を、油浴中で、９０℃でＮ_２下の３０ｍＬの密封管内で１６時間攪拌した。得られた溶液を冷却し、水を加え、混合物を２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空内で濃縮し、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、５００ｍｇ（６７％）の表題化合物をオフホワイト固体として得た。 Example 81
N- (5-Hydroxypyridin-2-yl) -4- (1-methyl-1H-indazole-4-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (1-methyl-1H-indazole-4-yl) piperazine-1-carboxylate

4-Bromo-1-methyl-1H-indazole (500 mg, 2.37 mmol, 1.00 eq), tert-butylpiperazin-1-carboxylate (443 mg, 2.38 mmol, 1.00 eq) in toluene (10 mL) ), NaOtBu (343 mg, 1.50 eq), Dave Phos (9 mg, 0.01 eq), and Pd ₂ (dba) ₃ (22 mg, 0.02 mmol, 0.01 eq) in an oil bath. , 90 ° C. in a 30 mL sealed tube under _N2 for 16 hours. The resulting solution was cooled, water was added and the mixture was extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated in vacuo and purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 500 mg (67%) of the title compound as an off-white solid.

ジオキサン（１０ｍＬ）中の前のステップからの生成物（５００ｍｇ、１．５８ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら４Ｎ ＨＣｌ／ジオキサン（５ｍＬ）を滴下した。得られた溶液を、室温で４時間攪拌した。溶液のｐＨ値を、ＮａＨＣＯ_３溶液でｐＨ７に調整した。得られた溶液を、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出し、有機層を混合、真空内で濃縮し、３００ｍｇ（８８％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 317
Step 2.1-Synthesis of Methyl-4- (Piperazine-1-yl) -1H-Indazole

4N HCl / dioxane (5 mL) was added dropwise to a solution of product (500 mg, 1.58 mmol, 1.00 eq) from the previous step in dioxane (10 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to pH 7 with a NaHCO ₃ solution. The resulting solution was extracted with 2 × 30 mL CH ₂ Cl ₂ and the organic layers were mixed and concentrated in vacuo to give 300 mg (88%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（６０ｍｇ、０．２８ｍｍｏｌ、１．００当量）、５－フルオロピリジン－２－イルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）の溶液を、室温で、４０ｍＬバイアル内で１６時間攪拌した。得られた溶液に水を加え、混合物を、２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１１０ｍｇ（８５％）の表題化合物をオフホワイト固体として得た。 LC-MS: (ES, m / z): 217
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (1-methyl-1H-indazole-4-yl) piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (60 mg, 0.28 mmol, 1.00 eq), 5-fluoropyridin-2-yl N-5-[(tert-butyldimethylsilyl) oxy ] A solution of pyridine-2-ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) and TEA (84 mg, 0.83 mmol, 3.00 eq) was stirred at room temperature in a 40 mL vial for 16 hours. Water was added to the resulting solution and the mixture was extracted with 2 x 30 mL CH ₂ Cl ₂ . The organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 110 mg (85%) of the title compound as an off-white solid.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１１０ｍｇ、０．２４ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌し、次いで真空内で濃縮した。粗生成物（１１０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大５０．０％の２０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５９．０ｍｇ（７１％）の表題化合物をオフホワイトの固体として得た。 LC-MS (ES, m / z): 467
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (1-methyl-1H-indazole-4-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (110 mg, 0.24 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (110 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 50.0% 20.0% ACN in 8 minutes); The detector was purified by preparative-HPLC under UV 254/220 nm conditions to give 59.0 mg (71%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 353
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.91 (s, 1H), 8.10 (d, J = 0.9Hz, 1H), 7.79 (d) , J = 2.9Hz, 1H), 7.59 (d, J = 8.9Hz, 1H), 7.29-7.17 (m, 1H), 7.14-7.13 (m, 2H) , 6.47 (d, J = 7.4Hz, 1H), 3.98 (s, 3H), 3.67 (m, 4H), 3.21m, 4H).

ステップ１．ｔｅｒｔ－ブチル４－（１－メチル－１Ｈ－インダゾール－６－イル）ピペラジン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の６－ブロモ－１－メチル－１Ｈ－インダゾール（５００ｍｇ、２．３７ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチルピペラジン－１－カルボキシレート（４４３ｍｇ、２．３８ｍｍｏｌ、１．００当量）、ＮａＯｔＢｕ（３４３ ｍｇ、１．５０当量）、ＤａｖｅＰｈｏｓ（９ｍｇ、０．０１当量）、およびＰｄ_２（ｄｂａ）_３（２２ｍｇ、０．０２ｍｍｏｌ、０．０１当量）の溶液を、油浴中で、９０℃でＮ_２下の３０ｍＬの密封管内で１６時間攪拌した。得られた溶液を、２×３０ｍＬのＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、６００ｍｇ（８０％）の表題化合物を白色固体として得た。 Example 82
N- (5-Hydroxypyridin-2-yl) -4- (1-methyl-1H-indazole-6-yl) piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (1-methyl-1H-indazole-6-yl) piperazine-1-carboxylate

6-bromo-1-methyl-1H-indazole (500 mg, 2.37 mmol, 1.00 eq), tert-butylpiperazin-1-carboxylate (443 mg, 2.38 mmol, 1.00 eq) in toluene (10 mL) ), NaOtBu (343 mg, 1.50 eq), Dave Phos (9 mg, 0.01 eq), and Pd ₂ (dba) ₃ (22 mg, 0.02 mmol, 0.01 eq) in an oil bath. , 90 ° C. in a 30 mL sealed tube under _N2 for 16 hours. The resulting solution was extracted with 2 x 30 mL EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 600 mg (80%) of the title compound as a white solid.

ジオキサン（１０ｍＬ）中の前のステップからの生成物（６００ｍｇ、１．９０ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら４Ｎ ＨＣｌ／ジオキサン（５ｍＬ）を加えた。得られた溶液を、室温で４時間攪拌した。溶液のｐＨ値を、ＮａＨＣＯ_３溶液でｐＨ７に調整した。得られた溶液を、２×３０ ｍＬのＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮し、１００ｍｇ（２４％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 317
Step 2.1-Synthesis of Methyl-6- (Piperazine-1-yl) -1H-Indazole

To a solution of product (600 mg, 1.90 mmol, 1.00 eq) from the previous step in dioxane (10 mL) was added 4N HCl / dioxane (5 mL) with stirring. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to pH 7 with a NaHCO ₃ solution. The resulting solution was extracted with 2 x 30 mL EtOAc, the organic layers were mixed and concentrated in vacuo to give 100 mg (24%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前のステップからの生成物（１００ｍｇ、０．４６ｍｍｏｌ、１．００当量）、５－フルオロピリジン－２－イルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）の溶液を、室温で、４０ｍＬバイアル内で１６時間攪拌した。得られた溶液に水を加え、混合物を２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を真空内で濃縮した。残留物を、ＥｔＯＡｃ／ヘキサン（１／２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１０５ｍｇ（４９％）の表題化合物をオフホワイト固体として得た。 LC-MS (ES, m / z): 217
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (1-methyl-1H-indazole-6-yl) piperazine-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (100 mg, 0.46 mmol, 1.00 eq), 5-fluoropyridin-2-yl N-5-[(tert-butyldimethylsilyl) oxy ] A solution of pyridine-2-ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) and TEA (84 mg, 0.83 mmol, 3.00 eq) was stirred at room temperature in a 40 mL vial for 16 hours. Water was added to the resulting solution and the mixture was extracted with 2 x 30 mL EtOAc. The mixed organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/2) to give 105 mg (49%) of the title compound as an off-white solid.

ＴＨＦ（４ｍＬ）中の前のステップからの生成物（１０５ｍｇ、０．２３ｍｍｏｌ、１．００当量）の溶液に、攪拌しながら２Ｎ ＨＣｌ水溶液（２ｍＬ）を滴下した。得られた溶液を、室温で２時間攪拌した。得られた混合物を真空内で濃縮した。粗生成物（１０５ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３）、およびＡＣＮ（８分間で最大４５．０％の１０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５６．９ｍｇ（７２％）の表題化合物をオフホワイトの固体として得た。 LC-MS (ES, m / z): 467
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (1-methyl-1H-indazole-6-yl) piperazine-1-carboxamide

A 2N HCl aqueous solution (2 mL) was added dropwise to a solution of the product (105 mg, 0.23 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. Crude product (105 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ), and ACN (up to 45.0% 10.0% ACN in 8 minutes); Purification by preparative-HPLC under conditions of detector, UV254 / 220 nm gave 56.9 mg (72%) of the title compound as an off-white solid.

LC-MS (ES, m / z): 353
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.93 (s, 1H), 7.84-7.75 (m, 2H), 7.57 (m, 2H) ), 7.13 (m, 1H), 6.95 (m, 2H), 3.93 (s, 3H), 3.62 (m, 4H), 3.21 (m, 4H).

ステップ１．４－（３，５，６－トリフルオロピリジン－２－イル）－Ｎ－（５－ヒドロキシピリジン－２－イル）ピペラジン－１－カルボキサミドの合成

２Ｎ ＨＣｌ水溶液（２ｍＬ）およびＴＨＦ（５ｍＬ）中のＮ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－４－（３，５，６－トリフルオロ－ピリジン－２－イル）ピペラジン－１－カルボキサミド（実施例７９の合成と同様に調製した；１００ｍｇ、０．２１ｍｍｏｌ、１．００当量）の溶液を、室温で２時間攪拌した。得られた混合物を真空内で濃縮した。粗生成物（１２０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ ｍＭ ＮＨ_４ＨＣＯ_３＋０．１％ＮＨ_３．Ｈ_２Ｏ）、およびＡＣＮ（８分間で最大６０．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４８．７ｍｇ（６４％）の表題化合物を白色固体として得た。 Example 83
N- (5-Hydroxypyridin-2-yl) -4- (3,5,6-trifluoropyridine-2-yl) piperazine-1-carboxamide

Step 1.4-Synthesis of 3- (3,5,6-trifluoropyridine-2-yl) -N- (5-hydroxypyridin-2-yl) piperazine-1-carboxamide

N- [5-[(tert-butyldimethylsilyl) oxy] pyridine-2-yl] -4- (3,5,6-trifluoro-pyridine-2) in 2N HCl aqueous solution (2 mL) and THF (5 mL) -Il) A solution of piperazine-1-carboxamide (prepared in the same manner as in the synthesis of Example 79; 100 mg, 0.21 mmol, 1.00 equivalent) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. Crude product (120 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O), and ACN (up to 60. in 8 minutes. 0% 30.0% ACN); detector, UV254 / 220 nm conditions, preparative-HPLC purification to give 48.7 mg (64%) of the title compound as a white solid.

LC-MS (ES, m / z): 353.9
^{1 1} H NMR (300 MHz, Deuteronol-d ₄ ) δ 7.84 (d, J = 2.9 Hz, 1H), 7.70 (dt, J = 11.0, 7.8 Hz, 1H), 7.53 ( d, J = 8.9Hz, 1H), 7.22 (dd, J = 8.9, 2.9Hz, 1H), 3.68 (m, 4H), 3.49 (m, 4H).

ステップ１．ｔｅｒｔ－ブチル４－（５－フルオロピリジン－２－イル）－１，４－ジアゼパン－１－カルボキシレートの合成

トルエン（１０ｍＬ）中の２－ブロモ－５－フルオロピリジン（１ｇ、５．６８ｍｍｏｌ、１．１４当量）、ｔｅｒｔ－ブチル１，４－ジアゼパン－１－カルボキシレート（１ｇ、４．９９ｍｍｏｌ、１．００当量）、Ｐｄ_２（ｄｂａ）_３（４６ｍｇ、０．０５ｍｍｏｌ、０．０１当量）、ＢＩＮＡＰ （３１ｍｇ、０．０５ｍｍｏｌ、０．０１当量）、ＮａＯｔＢｕ（２ｇ、２０．８３ｍｍｏｌ、４．１ ７当量）の溶液を、３０ ｍＬの密封チューブ内で、９０℃で一晩攪拌した。次いで、反応物を、水を加えることによりクエンチした。得られた溶液をＥｔＯＡｃで抽出し、有機層を混合し、真空内で濃縮した。残留物を、ＥｔＯＡｃ／石油エーテル（１：６）を使用してシリカゲルクロマトグラフィーで精製し、１．１ｇ（７５％）の表題化合物を黄色の油として得た。 Example 84
4- (5-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (5-fluoropyridin-2-yl) -1,4-diazepan-1-carboxylate

2-Bromo-5-fluoropyridine (1 g, 5.68 mmol, 1.14 eq) in toluene (10 mL), tert-butyl 1,4-diazepan-1-carboxylate (1 g, 4.99 mmol, 1.00) Equivalent), Pd ₂ (dba) ₃ (46 mg, 0.05 mmol, 0.01 equivalent), BINAP (31 mg, 0.05 mmol, 0.01 equivalent), NaOtBu (2 g, 20.83 mmol, 4.17 equivalent) The solution was stirred at 90 ° C. overnight in a 30 mL sealed tube. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc, the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc / petroleum ether (1: 6) to give 1.1 g (75%) of the title compound as a yellow oil.

LC-MS: (ES, m / z): 296.3
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 8.05 to 7.96 (m, 1H), 7.42 (tt, J = 8.8, 2.8 Hz, 1H), 6.66 (dd) , J = 9.3, 3.3 Hz, 1H), 3.67 (q, J = 6.5 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.46 (dt) , J = 17.2, 5.7 Hz, 2H), 3.20 (dt, J = 20.5, 5.9 Hz, 2H), 1.75 (dt, J = 21.8, 5.9) Hz, 2H), 1.29 to 1.21 (m, 9H).

４Ｎ ＨＣｌ／ジオキサン（５ｍＬ）中の前のステップからの生成物（１．１ｇ、３．７２ｍｍｏｌ、１．００当量）の溶液を、室温で、５０ｍＬの丸底フラスコ内で２時間攪拌した。得られた混合物を真空内で濃縮した。ｐＨを、ＮａＨＣＯ_３溶液でｐＨ８～９に調整した。得られた溶液を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合した。溶媒を除去して、４８０ｍｇ（６６％）の表題化合物を黄色の油として得た。 Step 2.1-Synthesis of 5- (5-fluoropyridin-2-yl) -1,4-diazepan

A solution of the product (1.1 g, 3.72 mmol, 1.00 eq) from the previous step in 4N HCl / dioxane (5 mL) was stirred at room temperature in a 50 mL round bottom flask for 2 hours. The resulting mixture was concentrated in vacuo. The pH was adjusted to pH 8-9 with a NaHCO ₃ solution. The resulting solution was extracted with CH ₂ Cl ₂ and mixed with an organic layer. The solvent was removed to give 480 mg (66%) of the title compound as a yellow oil.

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップからの生成物（６５ｍｇ、０．３３ｍｍｏｌ、１．２１当量）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（２００ｍｇ、１．９８ｍｍｏｌ、７．１８当量）の溶液を、５０ｍＬ丸底フラスコ内で、室温で一晩攪拌した。次いで、反応物を、水を加えることによりクエンチした。得られた溶液を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合し、真空内で濃縮し、１１０ｍｇ（８９％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 196.2
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-fluoropyridine-2-yl) -1,4-diazepan-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (10 mL) (65 mg, 0.33 mmol, 1.21 eq), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridine-2 -A solution of ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) and Et 3N ₍ 200 mg, 1.98 mmol, 7.18 eq) was stirred in a 50 mL round bottom flask overnight at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with CH ₂ Cl ₂ , mixed with an organic layer and concentrated in vacuo to give 110 mg (89%) of the title compound as a white solid.

２Ｎ ＨＣｌ（２ｍＬ）およびＴＨＦ（５ｍＬ）中の前のステップからの生成物（１１０ｍｇ、０．２５ ｍｍｏｌ、１．００当量）の溶液を、５０ｍＬ丸底フラスコ内で２時間、室温で攪拌した。得られた混合物を真空内で濃縮した。粗生成物を、機器「Ａ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大２５．０％の２．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、４２．４ ｍｇ（５２％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 446.2
Step 4.4 Synthesis of 4- (5-fluoropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

A solution of the product (110 mg, 0.25 mmol, 1.00 eq) from the previous step in 2N HCl (2 mL) and THF (5 mL) was stirred in a 50 mL round bottom flask for 2 hours at room temperature. The resulting mixture was concentrated in vacuo. Crude products, instrument "A"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 25.0% 2.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under 220 nm conditions gave 42.4 mg (52%) of the title compound as a white solid.

LC-MS (ES, m / z): 332.3
^{1 1} H NMR (300 Mhz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.48 (s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.75 (d) , J = 2.9Hz, 1H), 7.53 to 7.34 (m, 2H), 7.08 (dd, J = 8.9, 3.0Hz, 1H), 6.68 (dd, J = 9.4, 3.4Hz, 1H), 3.70 (m, 2H), 3.59 (m, 4H), 3.38 (m, 2H), 1.83 (m, 2H).

ステップ１．Ｔｅｒｔ－ブチル４－（５－クロロピリジン－２－イル）－１，４－ジアゼパン－１－カルボキシレートの合成

ＮＭＰ（５ｍＬ）中の５－クロロ－２－フルオロピリジン（１．３１ｇ、９．９６ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチル１，４－ジアゼパン－１－カルボキシレート（２ｇ、９．９９ｍｍｏｌ、１．００当量）、およびＤＩＰＥＡ（２ｍＬ）の溶液を、３０ｍＬ密封管内で、９０℃で一晩攪拌した。次いで、反応物を、水を加えることによりクエンチした。得られた溶液を、ＥｔＯＡｃで抽出し、有機層を混合した。得られた混合物を真空内で濃縮した。残留物を、ＥｔＯＡｃ／石油エーテル（１：６）を使用してシリカゲルカラムクロマトグラフィーで精製し、１．４ｇ（４５％）の表題化合物を白色固体として得た。 Example 85
4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

Step 1. Synthesis of tert-butyl 4- (5-chloropyridin-2-yl) -1,4-diazepan-1-carboxylate

5-Chloro-2-fluoropyridine (1.31 g, 9.96 mmol, 1.00 eq) in NMP (5 mL), tert-butyl 1,4-diazepan-1-carboxylate (2 g, 9.99 mmol, 1) The solution of .00 eq) and DIPEA (2 mL) was stirred in a 30 mL sealed tube at 90 ° C. overnight. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc and mixed with an organic layer. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1: 6) to give 1.4 g (45%) of the title compound as a white solid.

LC-MS (ES, m / z): 312.0
^{1 1} H NMR (300Mhz, DMSO-d ₆ ) δ 8.03 (d, J = 2.8Hz, 1H), 7.51 (dt, J = 9.1, 2.1Hz, 1H), 6.69 ( dd, J = 9.1, 0.7 Hz, 1H) 3.75 to 3.62 (m, 2H), 3.58 (t, J = 6.0Hz, 2H), 3.46 (dt, J = 17.9, 5.8 Hz, 2H) 3.33 to 3.12 (m, 2H), 1.74 (dt, J = 16.8, 5.7 Hz, 2H), 1.25 (D, J = 23.5 Hz, 9H).

４Ｎ ＨＣｌ／ジオキサン（１０ｍＬ）中の前のステップからの生成物（１．４ ｇ、４．４９ ｍｍｏｌ、１．００当量）の溶液を、５０ｍＬ丸底フラスコ内で２時間、室温で攪拌した。得られた混合物を真空内で濃縮した。溶液のｐＨ値を、ＮａＨＣＯ _３溶液でｐＨ８～９に調整した。得られた混合物を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合した。溶媒を除去して、８５０ｍｇ（８９％）の表題化合物を黄色の油として得た。 Step 2.1-Synthesis of 5- (5-chloropyridin-2-yl) -1,4-diazepan

A solution of the product (1.4 g, 4.49 mmol, 1.00 eq) from the previous step in 4N HCl / dioxane (10 mL) was stirred in a 50 mL round bottom flask for 2 hours at room temperature. The resulting mixture was concentrated in vacuo. The pH value of the solution was adjusted to pH 8-9 with a NaHCO ₃ solution. The obtained mixture was extracted with CH ₂ Cl ₂ and the organic layer was mixed. The solvent was removed to give 850 mg (89%) of the title compound as a yellow oil.

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前のステップからの生成物（７０ｍｇ、０．３３ｍｍｏｌ、１．２０当量）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＥｔ_３Ｎ（２００ｍｇ、１．９８ｍｍｏｌ、７．１８当量）の溶液を、５０ｍＬ丸底フラスコ内で、室温で一晩攪拌した。次いで、反応物を、水を加えることによりクエンチした。得られた溶液を、ＣＨ_２Ｃｌ_２で抽出し、有機層を混合し、真空内で濃縮し、１００ｍｇ（７８％）の表題化合物を白色固体として得た。 LC-MS: (ES, m / z): 212.0
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (5-chloropyridine-2-yl) -1,4-diazepan-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (10 mL) (70 mg, 0.33 mmol, 1.20 eq), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridine-2 -A solution of ylcarbamate (100 mg, 0.28 mmol, 1.00 eq) and Et 3N ₍ 200 mg, 1.98 mmol, 7.18 eq) was stirred in a 50 mL round bottom flask overnight at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with CH ₂ Cl ₂ , mixed with an organic layer and concentrated in vacuo to give 100 mg (78%) of the title compound as a white solid.

２Ｎ ＨＣｌ（２ｍＬ）およびＴＨＦ（５ｍＬ）中の前のステップからの生成物（１００ ｍｇ、０．２２ ｍｍｏｌ、１．００当量）の溶液を、５０ｍＬ丸底フラスコ内で２時間、室温で攪拌した。得られた混合物を真空内で濃縮した。粗生成物を、機器「Ａ」；カラム「Ｄ」；移動相、水（０．１％ＦＡ）およびＡＣＮ（７分間で最大３５．０％の２．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、２６．１ｍｇ（３５％）の表題化合物を白色固体として得た。 LC-MS (ES, m / z): 462.2
Step 4.4 Synthesis of 4- (5-chloropyridin-2-yl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

A solution of the product (100 mg, 0.22 mmol, 1.00 eq) from the previous step in 2N HCl (2 mL) and THF (5 mL) was stirred in a 50 mL round bottom flask for 2 hours at room temperature. .. The resulting mixture was concentrated in vacuo. Crude products, instrument "A"; column "D"; mobile phase, water (0.1% FA) and ACN (up to 35.0% 2.0% ACN in 7 minutes); detector, UV254 / Purification by preparative-HPLC under conditions of 220 nm gave 26.1 mg (35%) of the title compound as a white solid.

LC-MS: (ES, m / z): 348.3
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.49 (s, 1H), 8.01 (d, J = 2.7Hz, 1H), 7.75 (d) , J = 2.9Hz, 1H), 7.55-7.42 (m, 2H), 7.08 (dd, J = 8.9, 3.0Hz, 1H), 6.70 (d, J = 9.2Hz, 1H), 3.72 (m, 2H), 3.60 (m, 4H), 3.39 (m, 2H), 1.82 (m, 2H).

ステップ１．ｔｅｒｔ－ブチル４－［５－（トリフルオロメチル）ピリジン－２－イル］－１，４－ジアゼパン－１－カルボキシレートの合成

２－ブロモ－５－（トリフルオロメチル）ピリジン（１ｇ、４．４２ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチル１，４－ジアゼパン－１－カルボキシレート（１．１ｇ、５．４９ｍｍｏｌ、１．２０当量）トルエン（２０ｍＬ）中のＮａＯｔＢｕ（１．２８ｇ、３．００当量）、ＢＩＮＡＰ（１４０ｍｇ、０．２２ｍｍｏｌ、０．０５当量）、およびＰｄ_２（ｄｂａ）_３（２００ｍｇ、０．２２ｍｏｌ、０．０５当量）を、３０ｍＬの密封されたチューブ中、Ｎ_２下で１６時間、油浴中９０℃で攪拌した。次いで、反応混合物を、水で希釈し、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルクロマトグラフィーで精製し、１．２ｇ（７９％）の表題化合物をオフホワイトの固体として得た。 Example 86
N- (5-Hydroxypyridin-2-yl) -4- [5- (trifluoromethyl) pyridin-2-yl] -1,4-diazepan-1-carboxamide

Step 1. Synthesis of tert-butyl 4- [5- (trifluoromethyl) pyridin-2-yl] -1,4-diazepan-1-carboxylate

2-bromo-5- (trifluoromethyl) pyridine (1 g, 4.42 mmol, 1.00 eq), tert-butyl 1,4-diazepan-1-carboxylate (1.1 g, 5.49 mmol, 1.20) Equivalents) NaOtBu (1.28 g, 3.00 equivalents) in toluene (20 mL), BINAP (140 mg, 0.22 mmol, 0.05 equivalents), and Pd ₂ (dba) ₃ (200 mg, 0.22 mol, 0. 05 eq) was stirred in a 30 mL sealed tube under _N2 for 16 hours in an oil bath at 90 ° C. The reaction mixture was then diluted with water and extracted with 2 x 50 mL EtOAc. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc / Hexanes (1/1) to give 1.2 g (79%) of the title compound as an off-white solid.

２５０ｍＬの丸底フラスコにおいて、ジオキサン（１０ｍＬ）中の前ステップからの生成物（１．２ｇ、３．４７ｍｍｏｌ、１．００当量）の溶液に、４Ｎ ＨＣｌ／ジオキサン（５ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で４時間攪拌した。溶液のｐＨ値を、ＮａＨＣＯ_３で７に調整した（２ｍｏｌ／Ｌ）。得られた混合物を、２×５０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルクロマトグラフィーで精製し、０．８ｇ（９４％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 346.15.
Step 2.1-Synthesis of 5- [5- (trifluoromethyl) pyridin-2-yl] -1,4-diazepan

In a 250 mL round bottom flask, 4N HCl / dioxane (5 mL) was added dropwise to a solution of the product (1.2 g, 3.47 mmol, 1.00 eq) from the previous step in dioxane (10 mL) with stirring. .. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to 7 with NaHCO ₃ (2 mol / L). The resulting mixture was extracted with 2 x 50 mL EtOAc. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc / Hexanes (1/1) to give 0.8 g (94%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前ステップからの生成物（８１ｍｇ、０．３３ｍｍｏｌ、１．２０当量）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）の溶液を、４０ｍＬバイアルにおいて室温で１６時間攪拌した。得られた溶液を、水で希釈し、２×２０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１００ｍｇ（７３％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 246.20.
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- [5- (trifluoromethyl) pyridin-2-yl] -1,4-diazepan-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (81 mg, 0.33 mmol, 1.20 eq), 4-fluorophenyl N-5-[(tert-butyldimethylsilyl) oxy] pyridine-2- A solution of ilcarbamate (100 mg, 0.28 mmol, 1.00 eq) and TEA (84 mg, 0.83 mmol, 3.00 eq) was stirred in a 40 mL vial at room temperature for 16 hours. The resulting solution was diluted with water and extracted with 2 x 20 mL CH ₂ Cl ₂ . The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 100 mg (73%) of the title compound as an off-white solid.

１００ｍＬの丸底フラスコにおいて、ＴＨＦ（４ｍＬ）中の前ステップからの生成物（１００ｍｇ、０．２０ｍｍｏｌ、１．００当量）の溶液に、２ＭのＨＣｌ（２ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌した。これを真空内で濃縮した。粗生成物（１００ｍｇ）を、機器「Ａ」カラム「Ａ」；移動相、水（１０ｍＭ ＮＨ_４ＨＣＯ_３）およびＡＣＮ（８分で最大５０．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５０ｍｇ（６５％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 496.05.
Step 4. Synthesis of N- (5-hydroxypyridin-2-yl) -4- [5- (trifluoromethyl) pyridin-2-yl] -1,4-diazepan-1-carboxamide

In a 100 mL round bottom flask, 2 M HCl (2 mL) was added dropwise to a solution of the product (100 mg, 0.20 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours. This was concentrated in vacuo. Crude product (100 mg), instrument "A" column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (up to 50.0% 30.0% ACN in 8 minutes); detector, Purification by preparative-HPLC under UV254 / 220 nm conditions gave 50 mg (65%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 382.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.41 (s, 1H), 8.52 (s, 1H), 8.37 to 8.30 (m, 1H), 7.78 to 7.66 ( m, 2H), 7.42 (d, J = 9.0Hz, 1H), 7.05 (dd, J = 8.9, 3.0Hz, 1H), 6.81 (d, J = 9.0Hz) , 1H), 3.80 (m, 2H), 3.66 (m, 4H), 3.42 (m, 2H), 1.84 (m, 2H).

ステップ１．ｔｅｒｔ－ブチル－４－（３，４－ジフルオロフェニル）－１，４－ジアゼパン－１－カルボキシレートの合成

トルエン（２０ｍＬ）中の４－ブロモ－１，２－ジフルオロベンゼン（１ｇ、５．１８ｍｍｏｌ、１．００当量）、ｔｅｒｔ－ブチル１，４－ジアゼパン－１－カルボキシレート（１．２５ｇ、６．２４ｍｍｏｌ、１．２０当量）、ＮａＯｔＢｕ（１．５ｇ、３．００当量）、ＢＩＮＡＰ（１６０ｍｇ、０．２６ｍｍｏｌ、０．０５当量）、およびＰｄ_２（ｄｂａ）_３（２４０ｍｇ、０．２６ｍｍｏｌ、０．０５当量）の溶液を、３０ｍＬの密封されたチューブ中、Ｎ_２下で１６時間、油浴中９０℃で攪拌した。次いで、混合物を、水で希釈し、２×６０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１．１ｇ（６８％）の表題化合物をオフホワイトの固体として得た。 Example 87
4- (3,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

Step 1. Synthesis of tert-butyl-4- (3,4-difluorophenyl) -1,4-diazepan-1-carboxylate

4-bromo-1,2-difluorobenzene (1 g, 5.18 mmol, 1.00 eq) in toluene (20 mL), tert-butyl 1,4-diazepan-1-carboxylate (1.25 g, 6.24 mmol). , 1.20 equivalents), NaOtBu (1.5 g, 3.00 equivalents), BINAP (160 mg, 0.26 mmol, 0.05 equivalents), and Pd ₂ (dba) ₃ (240 mg, 0.26 mmol, 0.05). The equivalent solution) was stirred in a 30 mL sealed tube under _N2 for 16 hours in an oil bath at 90 ° C. The mixture was then diluted with water and extracted with 2 x 60 mL EtOAc. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 1.1 g (68%) of the title compound as an off-white solid.

２５０ｍＬの丸底フラスコにおいて、ジオキサン（１０ｍＬ）中の前ステップからの生成物（１．１ｇ、３．５２ｍｍｏｌ、１．００当量）の溶液に、４ＮのＨＣｌ／ジオキサン（５ｍＬ）の溶液を攪拌しながら滴下した。得られた溶液を、室温で４時間撹拌した。溶液のｐＨ値を、ＮａＨＣＯ_３でｐＨ７に調整した（２ｍｏｌ／Ｌ）。得られた溶液を２×５０ｍＬのＥｔＯＡｃで抽出し、混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、０．５ｇ（６７％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 313
Step 2.1-Synthesis of (3,4-difluorophenyl) -1,4-diazepan

In a 250 mL round bottom flask, stir a solution of 4N HCl / dioxane (5 mL) into a solution of the product (1.1 g, 3.52 mmol, 1.00 eq) from the previous step in dioxane (10 mL). While dripping. The resulting solution was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to pH 7 with NaHCO ₃ (2 mol / L). The resulting solution was extracted with 2 x 50 mL EtOAc and the mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 0.5 g (67%) of the title compound as an off-white solid.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の前ステップからの生成物（７０ｍｇ、０．３３ｍｍｏｌ、１．２０当量）、４－フルオロフェニルＮ－（５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル）カルバメート（１００ｍｇ、０．２８ｍｍｏｌ、１．００当量）、およびＴＥＡ（８４ｍｇ、０．８３ｍｍｏｌ、３．００当量）の溶液を、４０ｍＬのフラスコにおいて室温で１６時間撹拌した。次いで、混合物を水で希釈し、得られた溶液を２×３０ｍＬのＣＨ_２Ｃｌ_２で抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／１）を使用してシリカゲルカラムクロマトグラフィーで精製し、１０５ｍｇ（８２％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 213
Step 3. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl] -4- (3,4-difluorophenyl) -1,4-diazepan-1-carboxamide

Product from previous step in CH ₂ Cl ₂ (5 mL) (70 mg, 0.33 mmol, 1.20 eq), 4-fluorophenyl N- (5-[(tert-butyldimethylsilyl) oxy] pyridine-2 -Il) A solution of carbamate (100 mg, 0.28 mmol, 1.00 eq) and TEA (84 mg, 0.83 mmol, 3.00 eq) was stirred in a 40 mL flask at room temperature for 16 hours. The mixture was then diluted with water and the resulting solution was extracted with 2 x 30 mL CH ₂ Cl ₂ . The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / Hexanes (1/1) to give 105 mg (82%) of the title compound as an off-white solid.

１００ｍＬの丸底フラスコにおいて、ＴＨＦ（４ｍＬ）中の前ステップからの生成物（１０５ｍｇ、０．２３ｍｍｏｌ、１．００当量）の溶液に、２ＭのＨＣｌ水溶液（２ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空内で濃縮した。粗生成物（１０５ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ｍＭ ＮＨ_４ＨＣＯ_３）およびＡＣＮ（８分で最大５０．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５４．５ｍｇ（６９％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 463
Step 4.4 Synthesis of 4- (3,4-difluorophenyl) -N- (5-hydroxypyridin-2-yl) -1,4-diazepan-1-carboxamide

In a 100 mL round bottom flask, a 2 M aqueous HCl solution (2 mL) was added dropwise to a solution of the product (105 mg, 0.23 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (105 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (up to 50.0% 30.0% ACN in 8 minutes); detector Purified by preparative-HPLC at UV254 / 220 nm to give 54.5 mg (69%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 349.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.50 (s, 1H), 7.76 (d, J = 2.9Hz, 1H), 7.48 (d, J = 8.9Hz, 1H), 7.21 to 7.02 (m, 2H), 6.72 (ddd, J = 14.8, 6.9, 3.0Hz, 1H), 6.47 (dq) , J = 8.0, 2.3 Hz, 1H), 3.70 to 3.44 (m, 6H), 3.36 (m, 2H), 1.84 (m, 2H).

ステップ１．６－（ベンジルオキシ）ピリジン－３－オールの合成

ＣＨ_２Ｃｌ_２（５０ｍＬ）中の［６－（ベンジルオキシ）ピリジン－３－イル］ボロン酸（２ｇ、８．７３ｍｍｏｌ、１．００当量）および３０％のＨ_２Ｏ_２（２ｍＬ）の溶液を、１００ｍＬの丸底フラスコにおいて室温で一晩攪拌した。得られた混合物を水とＣＨ_２Ｃｌ_２との間で分配した。混合有機層を真空内で濃縮した。残渣をＥｔＯＡｃ／石油エーテル（１：３）を使用してシリカゲルカラムクロマトグラフィーで精製し、１．４ｇ（８０％）の表題化合物を白色固体として得た。 Example 88
5-Hydroxypyridin-2-yl 4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxylate

Step 1.6-Synthesis of (benzyloxy) Pyridine-3-ol

A solution of [6- (benzyloxy) pyridine-3-yl] boronic acid (2 g, 8.73 mmol, 1.00 eq) in CH ₂ Cl ₂ (50 mL) and 30% H ₂ O ₂ (2 mL). , Stir overnight at room temperature in a 100 mL round bottom flask. The resulting mixture was partitioned between water and CH ₂ Cl ₂ . The mixed organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1: 3) to give 1.4 g (80%) of the title compound as a white solid.

LC-MS: (ES, m / z): 202.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 7.69 (dd, J = 3.0, 0.6 Hz, 1H), 7.47-7.27 (m, 5H), 7.20 (dd, J = 8.8, 3.0Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 5.24 (s, 2H).

ＤＭＦ（３０ｍＬ）中の前ステップからの生成物（１．４ｇ、６．９６ｍｍｏｌ、１．００当量）、ＴＢＳＣ１（１．４ｇ、９．２７ｍｍｏｌ、１．３３当量）、およびイミダゾール（１ｇ、１４．７１ｍｍｏｌ、２．１１当量）の溶液を、１００ｍＬの丸底フラスコにおいて室温で２時間攪拌した。次いで、水の付加によって反応物をクエンチした。得られた溶液をエーテルで抽出し、有機層を混合した。得られた混合物を鹹水で洗浄した。有機層を真空内で濃縮した。残渣をＥｔＯＡｃ／石油エーテル（１：１０）を使用してシリカゲルカラムクロマトグラフィーで精製し、２．０ｇ（９１％）の表題化合物を無色の油として得た。 Step 2.2 Synthesis of 2- (benzyloxy) -5-[(tert-butyldimethylsilyl) oxy] pyridine

Products from the previous step in DMF (30 mL) (1.4 g, 6.96 mmol, 1.00 eq), TBSC1 (1.4 g, 9.27 mmol, 1.33 eq), and imidazole (1 g, 14. The solution (71 mmol, 2.11 eq) was stirred in a 100 mL round bottom flask at room temperature for 2 hours. The reactants were then quenched by the addition of water. The resulting solution was extracted with ether and mixed with an organic layer. The resulting mixture was washed with boiled water. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:10) to give 2.0 g (91%) of the title compound as a colorless oil.

ＭｅＯＨ（５０ｍＬ）中の前のステップからの生成物（２ｇ、６．３４ｍｍｏｌ、１．００当量）の溶液を、Ｈ_２下で１００ｍＬの丸底フラスコにおいて、Ｐｄ／Ｃ（２００ｍｇ）上で、室温で一晩攪拌した。固体を濾過により除去し、濾液を真空内で濃縮し、１．３ｇ（９１％）の表題化合物を黄色固体として得た。 LC-MS (ES, m / z): 316.3
Step 3.5-Synthesis of [(tert-butyldimethylsilyl) oxy] pyridin-2-ol

A solution of the product (2 g, 6.34 mmol, 1.00 eq) from the previous step in MeOH (50 mL) in a 100 mL _round bottom flask under H2 over Pd / C (200 mg) at room temperature. Stird overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo to give 1.3 g (91%) of the title compound as a yellow solid.

ＣＨ_２Ｃｌ_２（１０ｍＬ）中の前ステップからの生成物（２２５ｍｇ、１．００ｍｍｏｌ、１．００当量）およびトリホスゲン（３００ｍｇ、１．０１ｍｍｏｌ、１．０１当量）の溶液に、ピリジン（１ｍＬ）を０℃で攪拌しながら滴下した。０℃で３０分間攪拌した後、次いで、ＣＨ_２Ｃｌ_２（２ｍＬ）中の１－［５－（トリフルオロメチル）ピリジン－２－イル］ピペラジン（２３１ｍｇ、１．００ｍｍｏｌ、１．００当量）の溶液を付加した。得られた混合物を、室温で６時間攪拌した。次いで、水の付加によって反応物をクエンチした。得られた溶液をＣＨ_２Ｃｌ_２で抽出し、有機層を、混合し、真空内で濃縮した。残渣をＥｔＯＡｃ／石油エーテル（１：２）を使用してシリカゲルカラムクロマトグラフィーで精製し、１５０ｍｇ（３１％）の表題化合物を白色固体として得た。 LC-MS (ES, m / z): 226.0
Step 4.5-Synthesis of [(tert-butyldimethylsilyl) oxy] pyridin-2-yl 4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxylate

Pyridine (1 mL) in a solution of the product (225 mg, 1.00 mmol, 1.00 eq) from the previous step and triphosgene (300 mg, 1.01 mmol, 1.01 eq) in CH ₂ Cl ₂ (10 mL). The mixture was added dropwise at 0 ° C. with stirring. After stirring at 0 ° C. for 30 minutes, then 1- [5- (trifluoromethyl) pyridin-2-yl] piperazine (231 mg, 1.00 mmol, 1.00 eq) in CH ₂ Cl ₂ (2 mL). The solution was added. The resulting mixture was stirred at room temperature for 6 hours. The reactants were then quenched by the addition of water. The resulting solution was extracted with CH ₂ Cl ₂ and the organic layers were mixed and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1: 2) to give 150 mg (31%) of the title compound as a white solid.

ＴＨＦ（５ｍＬ）中の前ステップからの生成物（１５０ｍｇ、０．３１ｍｍｏｌ、１．００当量）および２ＮのＨＣｌ（２ｍＬ）水溶液の溶液を、５０ｍＬの丸底フラスコにおいて室温で２時間攪拌した。得られた混合物を、真空内で濃縮した。粗生成物を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ｍＭ ＮＨ_４ＨＣＯ_３）およびＡＣＮ（８分で最大５７．０％の３０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５０．１ｍｇ（４４％）の表題化合物を白色固体として得た。 LC-MS (ES, m / z): 483.4
Step 5.5 Synthesis of 5-hydroxypyridin-2-yl 4- [5- (trifluoromethyl) pyridin-2-yl] piperazine-1-carboxylate

A solution of the product from the previous step (150 mg, 0.31 mmol, 1.00 eq) in THF (5 mL) and a 2N aqueous solution of HCl (2 mL) was stirred in a 50 mL round bottom flask at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. Crude products, instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (up to 57.0% 30.0% ACN in 8 minutes); detector, UV254 / Purification by preparative-HPLC under conditions of 220 nm gave 50.1 mg (44%) of the title compound as a white solid.

LC-MS (ES, m / z): 368.9
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ9.87 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 7.84 (m, 2H), 7.28 (dd, dd, J = 8.7, 3.1 Hz, 1H), 7.00 (m, 2H), 3.91 to 3.70 (m, 6H), 3.56 to 3.53 (m, 2H).

ステップ１．Ｎ－［５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イル］－［１，１－ビフェニル］－３－カルボキサミドの合成

ＣＨ_２Ｃｌ_２（５ｍＬ）中の［１，１－ビフェニル］－３－カルボン酸（１９８ｍｇ、１．００ｍｍｏｌ、１．００当量）、ＥＤＣＩ（２３０ｍｇ、１．２０ｍｍｏｌ、１．２０当量）、４－ジメチルアミノピリジン（１２２ｍｇ、１．００ｍｍｏｌ、１．００当量）、５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－アミン（２２４ｍｇ、１．００ｍｍｏｌ、１．００当量）の溶液を、４０ｍＬバイアルにおいて１６時間室温で攪拌した。次いで、混合物を、水で希釈し、２×２０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空内で濃縮した。残渣をＥｔＯＡｃ／ヘキサン（１／２）を使用して分取ＴＬＣで精製し、２５０ｍｇ（６１％）の表題化合物を淡黄色固体として得た。 Example 89
N- (5-Hydroxypyridin-2-yl)-[1,1-biphenyl] -3-carboxamide

Step 1. Synthesis of N- [5-[(tert-butyldimethylsilyl) oxy] pyridin-2-yl]-[1,1-biphenyl] -3-carboxamide

[1,1-biphenyl] -3-carboxylic acid (198 mg, 1.00 mmol, 1.00 eq), EDCI (230 mg, 1.20 mmol, 1.20 eq), 4- in CH ₂ Cl ₂ (5 mL). 40 mL of a solution of dimethylaminopyridine (122 mg, 1.00 mmol, 1.00 eq), 5-[(tert-butyldimethylsilyl) oxy] pyridine-2-amine (224 mg, 1.00 mmol, 1.00 eq) The vial was stirred for 16 hours at room temperature. The mixture was then diluted with water and extracted with 2 x 20 mL EtOAc. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc / Hexanes (1/2) to give 250 mg (61%) of the title compound as a pale yellow solid.

１００ｍＬの丸底フラスコにおいて、ＴＨＦ（４ｍＬ）中の前ステップからの生成物（２５０ｍｇ、０．６２ｍｍｏｌ、１．００当量）の溶液に、２ＭのＨＣｌ（２ｍＬ）を攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空内で濃縮した。粗生成物（２５０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ｍＭ ＮＨ_４ＨＣＯ_３）およびＡＣＮ（８分で最大７４．０％の１０．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、１４９．４ｍｇ（８３％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 405.35
Step 2. Synthesis of N- (5-hydroxypyridin-2-yl)-[1,1-biphenyl] -3-carboxamide

In a 100 mL round bottom flask, 2 M HCl (2 mL) was added dropwise to a solution of the product (250 mg, 0.62 mmol, 1.00 eq) from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Crude product (250 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (up to 74.0% 10.0% ACN in 8 minutes); detector Purified by preparative-HPLC at UV254 / 220 nm to give 149.4 mg (83%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 291.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ10.75 (s, 1H), 9.80 (s, 1H), 8.31 (s, 1H), 8.11 to 7.90 (m, 3H) , 7.90 to 7.67 (m, 3H), 7.60 (m, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.26 (dd, J = 8). 9.9, 3.0Hz, 1H).

ステップ１．Ｎ－（５－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）ピリジン－２－イル）－４－（１－メチル－１Ｈ－ピラゾール－４－イル）ピペラジン－１－カルボキサミドの合成

ＣＨ_２Ｃｌ_２の溶液（５ｍＬ）中の１－（１－メチル－１Ｈ－ピラゾール－４－イル）ピペラジン（７０ｍｇ、０．４２ｍｍｏｌ、１．００当量）、４－フルオロフェニルＮ－５－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］ピリジン－２－イルカルバメート（１２０ｍｇ、０．３３ｍｍｏｌ、１．００当量）およびＥｔ_３Ｎ（１００ｍｇ、０．９９ｍｍｏｌ、３．００当量）を、室温で１６時間攪拌し、次いで、水で希釈し、２×３０ｍＬのＥｔＯＡｃで抽出した。混合有機層を、Ｎａ_２ＳＯ_４上で乾燥させ、真空下で濃縮して、表題化合物をオフホワイトの固体として得た。 Example 90
N- (5-Hydroxypyridin-2-yl) -4- (1-methyl-1H-pyrazole-4-yl) cyclohexane-1-carboxamide

Step 1. Synthesis of N- (5-((tert-butyldimethylsilyl) oxy) pyridin-2-yl) -4- (1-methyl-1H-pyrazole-4-yl) piperazine-1-carboxamide

1- (1-Methyl-1H-pyrazole-4-yl) piperazine (70 mg, 0.42 mmol, 1.00 eq) in a solution of CH ₂ Cl ₂ (5 mL), 4-fluorophenyl N-5-[((70 mg, 0.42 mmol, 1.00 eq)) tert-Butyldimethylsilyl) oxy] Pyridine- ₂ -ylcarbamate (120 mg, 0.33 mmol, 1.00 eq) and Et 3N (100 mg, 0.99 mmol, 3.00 eq) were stirred at room temperature for 16 hours. Then diluted with water and extracted with 2 x 30 mL EtOAc. The mixed organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give the title compound as an off-white solid.

ＴＨＦ（４ｍＬ）中の前ステップからの生成物の溶液に、２ｍＬの２ＭのＨＣｌを攪拌しながら滴下した。得られた溶液を、室温で２時間攪拌し、次いで、真空下で濃縮した。粗生成物（１１０ｍｇ）を、機器「Ａ」；カラム「Ａ」；移動相、水（１０ｍＭ ＮＨ_４ＨＣＯ_３）およびＡＣＮ（７分で最大２７．０％の２．０％ＡＣＮ）；検出器、ＵＶ２５４／２２０ｎｍの条件で、分取－ＨＰＬＣで精製し、５４．３ｍｇ（６８％）の表題化合物をオフホワイトの固体として得た。 LC-MS: (ES, m / z): 417.25
Step 2. Synthesis of N- (5-hydroxypyridin-2-yl) -4- (1-methyl-1H-pyrazole-4-yl) piperazine-1-carboxamide

2 mL of 2M HCl was added dropwise to the solution of the product from the previous step in THF (4 mL) with stirring. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. Crude product (110 mg), instrument "A"; column "A"; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (up to 27.0% 2.0% ACN in 7 minutes); detector Purified by preparative-HPLC at UV254 / 220 nm to give 54.3 mg (68%) of the title compound as an off-white solid.

LC-MS: (ES, m / z): 303.0
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ8.86 (s, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.26 (s, 1H), 7.22 to 7.06 (m, 2H), 3.70 (s, 3H), 3.52 (t, J = 5.0Hz, 4H), 2.80 ( t, J = 5.0Hz, 4H)

The following compounds can generally be made using the above methods. It is expected that these compounds, when made, will have the same activity as those made in the above Examples.

The activity of a compound in the compounds disclosed herein as being useful as a Des1 inhibitor and in the treatment of disease is exemplified in the assay below.

Biological Activity Assay Des1 Activity Assay The following are in vitro cell assays that can be used to assess the potential inhibitory activity of the compounds disclosed herein for Des1 as well as the disease-specific physiological consequences of Des1 inhibition. This is an example.

Jurkat T Cell Measurement of Dihydroceramide to Ceramide Conversion Jurkat clone E6-1 cells were grown and then seeded in 96-well plates at ¹⁰⁶ cells / mL (400 μL in each well). The cells were administered 100 μL of cell culture medium containing 50 μM NBD-C6-dihydroceramide (Des1 substrate) to give a final concentration of 10 μM substrate. The cells were incubated with the substrate at 4 ° C for 30 minutes. After incubation at 4 ° C., the cell suspension is centrifuged at 1200 rpm for 3 minutes and the cell pellet is 400 μL fresh containing either fenretinide (a known Des1 inhibitor control compound) or test sample at various concentrations. Resuspended in a medium. The final concentrations of control and test compounds were tested in the range 0-10 μM. The cells and compounds were incubated at 37 ° C. for 3 hours. After 3 hours of incubation, the plates are centrifuged at 4 ° C. for 3 minutes at 2500 g, followed by collection of 200 μL of supernatant, suitable for liquid chromatography / tandem mass spectrometry (LC / MS / MS) analysis. Transferred to a new 96-well plate with 300 μL of methanol containing an internal standard (internal standard: 500 nM labetalol and 100 nM alprazolum). The sample was vortexed for 2 minutes and then centrifuged at 3,220 g for 20 minutes. After centrifugation, 200 μL of the supernatant was transferred to a new 96-well plate for LC-MS / MS analysis to determine the amount of NBD-C6-ceramide (Des1 product) produced. Assays were typically performed in duplicate. A reduction of at least 30% compared to the vehicle control (0 μM test sample) indicates the active compound and a 75% reduction compared to the vehicle control is preferred. As an example, fenretinide exhibits a maximum half-dose inhibition concentration (IC50) of 100-250 nM, and some compounds described herein exhibit _IC50 values of less than 50 nM.

C2C12 myotube assay for Akt insulin-stimulated phosphorylation:
C2C12 myotubes were treated with 0.75 mM BSA-conjugated palmitate for 16 hours in the presence or absence of 7 non-zero concentrations of fenretinide (Des1 inhibitor control compound) or various test samples, followed by Then, it is stimulated with insulin (100 nM) for 10 minutes. The cells are then harvested, boiled in reduced SDS sample buffer and subjected to SDS-PAGE, followed by phosphorylated Act, total Act, and suitable by Western blot using a fluorescent conjugated secondary antibody. Load controls (eg, actin or GAPDH) are detected. Band intensity is quantified by the Odyssey Imaging System (Li-COR), but can also be done using HRP-conjugated secondary antibody / enhanced chemiluminescence or by colorimetric readout.

In addition, although currently contemplated for SDS-PAGE / immunoblot formats, this assay may be adapted to an ELISA or intracellular western (immunocytochemistry) format for higher throughput testing of compounds. A 30% increase compared to the vehicle control (0 μM test sample) indicates the active compound, a 50% increase compared to the control is preferred. As an example, fenretinide shows a maximum effective concentration (EC50) for increasing insulin-stimulated Akt phosphorylation in the presence of 600 nM palmitate. The Des1 inhibitors disclosed herein are expected to be effective in this assay.

Insulin resistance, dyslipidemia, and NAFLD / NASH rodent high-fat diet model:
The standard model for human hyperlipidemia and insulin resistance is mice fed a high-fat diet for several weeks. Test compounds are evaluated in this model as agents for restoring insulin sensitivity and lowering blood lipids. A chronic high-fat diet is fed to mice to simulate a standard Western diet in which calories increase from high-fat and carbohydrate intake. This and similar models of diet-induced obesity, insulin insensitivity, and elevated serum lipids and cholesterol include hyperlipidemia, type II diabetes, atherosclerosis, obesity, cardiovascular and liver disease in humans. Used as a mouse and rat model of pathology. It is understood that the diet can be changed to a "fast food diet" to include more atherogenic factors (eg, 2% cholesterol and 12% saturated fatty acids) in order to enhance the NASH phenotype. These models have been used as excellent predictors of efficacy in human clinical trials (PPAR and FXR agonists). Key endpoints (including collagen detection) used to assess the therapeutic activity of candidate Des1 inhibitors, including fasting blood glucose, insulin, triglycerides, cholesterol, hepatic steatosis, markers of liver inflammation, and fibrosis. Glucose and insulin resistance studies can also be performed. Glycosylated hemoglobin can also be measured as a more chronic marker of hyperglycemia. Liver steatosis (fatty liver) can be assessed by oil red O staining of liver sections and by quantitative determination of liver triglycerides. Des1 inhibitors have been shown to be effective in this assay, improving insulin sensitivity, lowering blood lipids, reducing or preventing the development of hepatic steatosis, and / or dyslipidemia, type II diabetes, atherosclerosis. It is expected to be generally effective on scales of pathology associated with sclerosis, obesity, cardiovascular disease, and / or liver disease such as NASH or NAFLD. In the case of NAFLD / NASH, the efficacy of Des1 inhibitors is FXR agonist, ASK1 inhibitor, ACC inhibitor, PPAR agonist, ileal bile acid transport inhibitor, DGAT2 inhibitor, FGF19 analog, FGF21 analog, NLRP3 inframa. It is also understood that co-administration with som inhibitors, ketohesoki kinase inhibitors, and caspase inhibitors can potentially enhance them. For type 2 diabetes, the efficacy of Des1 inhibitors includes metformin, GLP-1 analogs, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, meglycidins, PPAR agonists, SGLT2 inhibitors, and insulin. It is understood that co-administration of can be potentially enhanced. It is also understood that in the case of dyslipidemia, the efficacy of Des1 inhibitors can be potentially enhanced by co-administration with fibrates, niacin, omega-3 fatty acids, statins, bile resins, and PCSK9 inhibitors.

Measurement of in vivo activity in a model of atherosclerosis:
A major workhorse rodent model of atherosclerosis is a high-fat dieted ApoE-/-(ApoE knockout) mouse that produces atherosclerotic lesions that can be measured in various aspects of the aorta. be. As an example, 8-week-old male ApoE − / − mice are fed a high-fat diet for 30 days to establish atherosclerotic lesions. Animal controls are euthanized and assessed for aortic lesion status 30 days after a high-fat diet. Subsequently, the two groups of mice are switched to a standard solid feed diet for an additional 60 days, during which the animals are administered either a vehicle, a candidate Des1 inhibitor, or a reference control compound (eg, myriocin). .. Sixty days after dosing, the mice are fasted overnight and the perfused fixed aorta is dissected to allow lesion analysis of the aortic sinus, aortic arch, and abdominal bifurcation of the abdominal aorta. Morphological analysis of these three aortic sites is performed after the tissue has been subjected to Verhoeff staining (Gloros et al. (2008) Myriocin slows the progression of estabilized atherosclerotic lipids out. .49, 324-331).

The Des1 inhibitors disclosed herein would be expected to prevent or cause regression of established atherosclerotic lesions.

Measurement of in vitro cell anticancer activity:
PC3 prostate cancer, MCF7 ER + breast cancer cells, or various other cancer cell lines are cultured in DMEM (containing 10% fetal bovine serum and penicillin-streptomycin). Frozen aliquot cells are resuspended in 5 mL of warm medium and centrifuged at 200 g for 5 minutes. The supernatant is aspirated and the cell pellet is resuspended in 5 mL of medium. The cells are then grown in tissue culture flasks at 37 ° C. with 5% CO ₂ and subcultured four times before use if they are 80-90% confluent. The cells are then incubated with trypsin for 5 minutes to separate from cell culture flanks. Prior to treatment with the drug compound, cells are seeded in 96-well plates at 2,500 cells / well and incubated in a humidified incubator for the previous 24 hours with 5% CO ₂ at 37 ° C. Fenretinide (Des1 control inhibitor) or various test samples are diluted in medium to a final concentration in the range of 10 μM to 0 μM using DMSO as a vehicle control (0.1% final DMSO concentration). The cell culture supernatant is aspirated and replaced with medium containing either fenretinide or various test samples. Drug treatment is performed in overlapping wells. Cells are incubated with the drug compound at 37 ° C. for 72 hours at 5% CO ₂ in a humidified incubator prior to determining cell viability. After 72 hours of incubation with the compound, the cell culture supernatant is then aspirated from the wells and replaced with 100 μL of CellTiter Glo solution. Triple cell-free control wells containing only CellTiter solution are also included in each assay. The cells are then incubated in a humidified incubator for 1 hour at 5% CO ₂ at 37 ° C., where the absorbance is read at 490 nm by a microplate reader device. Background absorbance (obtained from cell-free control wells) is subtracted from each reading. To determine the inhibition percentage of cell viability, the absorbance reading for each drug treatment is expressed as a fraction of the vehicle control (0.1% DMSO) reading. For each drug concentration, the average (+/- SEM) is calculated and graphed using GraphPad Prism or other suitable scientific graphing package. The sigmoid curve is fitted to the data and used to calculate the IC50 for each compound. A reduction in cancer cell viability of at least 30% compared to the vehicle control (0 μM test sample) indicates the active compound, with a 50% reduction compared to the control preferred. The Des1 inhibitors disclosed herein are effective in reducing cancer cell viability and are therefore expected to be effective in the treatment of cancer.

Measurement of in vivo anticancer activity:
Human tumor xenografts in immunodeficient mice (eg, thymic nude mice) transplanted either sympathetically or ectopically are workhorses for predicting the clinical efficacy of candidate anticancer agents. Represents a model. As an example, in the case of ER + breast cancer, ovariectomized estrogen-treated (0.72 mg / 60 days 17β-estradiol (E2) time-release sc pellets) NU / NU mice (about 6 weeks old) are 5 × 10 ⁶ Individual MCF7 cells (ER + human cell line derived from breast cancer) are injected into the axial mammary fat pad. Tumors were measured by caliper 3 times per week until tumor volume ((L ² · W) / 2) reached 0.2 cm ³ , followed by the presence of standard therapeutic agents (eg, tamoxifen) in mice. Randomized to treatment groups with test compounds in the presence or absence. The active Des1 inhibitor would be expected to exhibit tumor growth inhibition or regression over a 28-day treatment period, indicating the potential anti-cancer activity of the test compound.

In addition, the test compound has the advantage of having a completely intact immune system (eg, MC38 model for colorectal cancer or KPC model for pancreatic ductal adenocarcinoma), so that it is syngeneic and / or genetically engineered for various tumors. Potential anti-cancer activity in the established mouse model can also be evaluated. Candidate Des1 inhibitors can inhibit the activity and / or recruitment of various cell types (eg, bone marrow-derived suppressor cells, regulatory T cells) that lead to immunosuppression in the tumor microenvironment, thus PD1, PD- Monochromic antibody therapeutics targeting L1, CTLA-4, CD47, and OX40, as well as indoleamine-2,3-di used to re-awaken the immune system to enable immunological attack of the tumor. It can have synergistic activity with various immune checkpoint inhibitors, including small molecules that target oxygenase 1 or arginase-1. Such therapies would be expected to produce anti-tumor immunity and potentially durable anti-tumor memory responses.

The Des1 inhibitors disclosed herein are expected to be effective as a single agent and in combination with standard of care therapy in the treatment of cancer.

Measurement of activity in an in vivo model of cystic fibrosis:
Gene disruption of cystic fibrosis transmembrane conduction regulator (CFTR) in mice reproduces some of the clinical manifestations of cystic fibrosis observed in patients and has become a workhorse pharmacological model for this disease. Since ceramide has been shown to accumulate in the lungs of CFTR (CFTR-KO) mouse knockouts and create an pro-inflammatory environment, pulmonary arachidonic acid (AA-promoting mediator) is a lipid precursor to docosahexaenoic acid (DHA). ) Is measured. A high AA / DHA ratio indicates an pro-inflammatory environment. It has been previously shown that fenretinide, a known Des1 inhibitor, normalizes this ratio in the lungs of CFTR-KO mice (and thus reduces inflammation) and reduces susceptibility to infection with Pseudomonas aeruginosa. （Ｇｕｉｌｂａｕｌｔ ｅｔ ａｌ．２００９ Ｃｙｓｔｉｃ ｆｉｂｒｏｓｉｓ ｆａｔｔｙ ａｃｉｄ ｉｍｂａｌａｎｃｅ ｉｓ ｌｉｎｋｅｄ ｔｏ ｃｅｒａｍｉｄｅ ｄｅｆｉｃｉｅｎｃｙ ａｎｄ ｃｏｒｒｅｃｔｅｄ ｂｙ ｆｅｎｒｅｔｉｎｉｄｅ．Ａｍ． Ｊ． Ｒｅｓｐｉｒ．Ｃｅｌｌ Ｍｏｌ．Ｂｉｏｌ．４１，１００－１０６、Ｇｕｉｌｂａｕｌｔ ｅｔ ａｌ．２００８ Ｆｅｎｒｅｔｉｎｉｄｅ ｃｏｒｒｅｃｔｓ ｎｅｗｌｙ ｆｏｕｎｄ ｃｅｒａｍｉｄｅ ｄｅｆｉｃｉｅｎｃｙ ｉｎ Cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 38, 47-56). Therefore, a candidate Des1 inhibitor can be tested in this CFTR-KO mouse model of cystic fibrosis, the primary endpoint being the AA / DHA ratio, as well as the inflammatory response to Pseudomonas aeruginosa loading and the ability to eliminate it. In the longer term, mice lacking CFTR develop substantial pulmonary fibrosis that can be histologically assessed by quantitative assessment of hydroxyproline in lung tissue (eg, sirius red or trichrome staining of lung tissue). ). The Des1 inhibitors disclosed herein are expected to normalize the ratio of lung AA to DHA, normalize the ratio of circulating AA to DHA, reduce lung inflammation, and reduce pulmonary fibrosis. Let's go.

Measurement of in vitro cell antifibrotic activity:
Normal and SSc (diffuse systemic sclerosis) skin fibroblasts are cultured in DMEM supplemented with 10% FBS and 1% antibiotic antifungal solution. Cells are pre-treated with various test samples (DMSO vehicle control, 0.1%) at 37 ° C. for 12-24 hours with fenretinide (Des1 inhibitor control compound) and concentrations ranging from 10 μM to 0 μM. Incubate in serum-free medium for 24 hours. Smad3 (a downstream signaling intermediate in the TGFβ pathway) as well as collagen (COL1A1) are measured as in vitro substitutes for the promoted fibrosis state. A reduction of at least 30% compared to the vehicle control (0 μM test sample) indicates the active compound, preferably a 50% reduction compared to the control. The Des1 inhibitors disclosed herein are expected to be effective in reducing the scale and markers of fibrosis.

Measurement of in vivo antifibrotic activity:
Various rodent models exist to assess the potential of test compounds in in vivo antifibrotic activity, including those representing fibrosis of lung, kidney, liver, and skin / connective tissue. As an example, and in the case of liver fibrosis, rodents (mouse or rat) were injected with CCl ₄ , hepatotoxin, followed by animals being randomized to the treatment group (pirfenidone used as a reference control compound). ), Evaluated 6-8 weeks after CCU injection. The primary measures of liver fibrosis for assessing the potential therapeutic efficacy of test compounds are liver function tests (eg, AST, ALT, bilirubin), hydroxyproline content in the liver, and liver histological sections. Includes Sirius Red Staining. An active Des1 inhibitor would be expected to substantially reduce the levels of sirius red staining in the liver, as well as hydroxyproline levels. The Des1 inhibitors disclosed herein would be expected to reduce fibrosis in a variety of organs, including liver, lungs, kidneys, heart, and skin.

Measures of disease-modifying activity in multiple sclerosis:
Includes myelin oligodendrocyte glycoprotein (MOG) (chronic progressive model) and proteolipoprotein (PLP (recurrence / remission model)), as well as those that are immunized with others that rely on adoptive cell transduction techniques. There are numerous mouse models of multiple sclerosis (MS). As an example, and in the case of the MOG chronic progressive model, chronic progressive in C57BL / 6 mice after immunization with an emulsion of MOG _35-55 / CFA or MOG _1-125 / CFA followed by injection of pertussis toxin. EAE occurs. This model is used to test the potential of compounds to prevent or alleviate EAE disease. It is performed with the aim of reversing the course of the disease and promoting recovery by administering the compound from the time of immunization (preventive treatment) or from the time of EAE onset (therapeutic treatment). Can be done. This model uses female C57BL / 6 mice 10-14 weeks old at the start of the study. Typically, EAE occurs 8-18 days after immunization. The development of EAE usually lasts 4 weeks (28 days) after immunization. Compounds can be assessed for their ability to reduce the severity or incidence of disease compared to reference control compounds (eg, fingolimod) (scoring limb weakness / paralysis and behavior, as well as demyelination. By both histopathology of the spinal cord card, including the degree of). Active Des1 inhibitors would be expected to reduce the severity of the disease (clinical score), the degree of spinal cord demyelination, inflammatory cell infiltrates into the spinal cord, and the number of apoptotic cells in the spinal cord. Active Des1 inhibitors include fingolimod (and other sphingosine-1-phosphate receptor regulators), teriflunomide, dimethyl fumarate, PAD4 inhibitors, anti-CD20 and anti-CD52 mAbs, natalizumab, glatiramer acetate, and interferon-β. Can be combined with other therapeutic agents for multiple sclerosis, including. The Des1 inhibitors disclosed herein will have disease-modifying activity in multiple sclerosis or will be expected to provide symptom relief.

Measurement of disease-modifying anti-rheumatic drug (DMARD) activity:
The collagen-induced arthritis (CIA) model has many immunological and pathological similarities with human rheumatoid arthritis (RA), involvement of local major histological compatibility, and complete class II-limited T-helper lymphocyte activity. Due to its morphology and histological lesion similarity, it is considered a suitable model for studying potential drugs that are active in human rheumatoid arthritis. Similar features to this CIA model found in RA patients are cartilage and bone erosion at the joint edges (as can be seen on radiographs), proliferative synovitis, and limb skeleton rather than central skeleton. Includes symmetrical involvement of small and medium peripheral joints. The compounds disclosed herein are described in Rosloniec EF et al. , "Collagen-Induced Arthritis," Currant Protocols in Immunology, Unit 15.5 (1993) tested for activity against autoimmune arthritis (eg, reduced disease severity or incidence). obtain. Compounds can be evaluated for their ability to reduce the severity or incidence of disease compared to reference control compounds (eg, dexamethasone) (both examination of joint appearance and their structure by histopathology). By). An active Des1 inhibitor would be expected to reduce the severity and / or incidence of disease in a collagen-induced arthritis model. Active Des1 inhibitors include various analgesics (including conventional NSAID and COX2 selective inhibitors), steroids, methotrexate, gold salts, hydroxychlorokin, PAD4 inhibitors, sulfasalazine, reflunomide, anti-TNFα, yanus kinase inhibitors, It can be administered in combination with abatacept, rituximab, and anakinra. The Des1 inhibitors disclosed herein would have disease-modifying activity in rheumatoid arthritis or would be expected to provide symptom relief.

Measurement of activity in Alzheimer's disease There are various animal models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A standard mouse model known in the art is a transgenic early-onset disease model for encoding a double variant of amyloid precursor protein 695 (KM670 / 671NL1V717F) under the control of the PrP gene promoter. , TgCRND8. These mice develop cortical Aβ ₄₂ and hyperphosphorylated Tau proteins that resemble some of the clinical features of Alzheimer's disease. Animals were treated with Des1 inhibitor for 4 months at 4 weeks of age, followed by postmortem evaluation of brain ceramide, Aβ ₄₂ and hyperphosphorylated Tau protein. Active Des1 inhibitors would be expected to reduce levels of brain ceramide, as well as Aβ ₄₂ and hyperphosphorylated Tau proteins that potentially cause disease. Des1 inhibitors can potentially be administered in combination with other therapeutic agents for Alzheimer's disease, including cholinesterase inhibitors and memantine. The Des1 inhibitors disclosed herein will have disease-modifying activity in Alzheimer's disease or will be expected to provide symptom relief.

Measurement of activity in amyotrophic lateral sclerosis:
The most commonly used animal model for amyotrophic lateral sclerosis (ALS) is a SOD1-G93A transgenic mouse with a phenotype that partially reproduces what is clinically observed in a patient. Mice develop paralysis of one or more limbs within a few months (with a decrease in grip strength in the longitudinal direction), and the major disease endpoints are grip strength, as well as assay for lipid peroxidase activity (MDA) in the spinal cord. , And astrocytosis (GFAP) in the ventral thalamus. Animals are administered Des1 inhibitors either early in the disease (approximately 12 weeks of age) or late in the disease (18-20 weeks of age), followed by in-life assessment (grip strength) and postmortem measurements. (Lipid peroxidase and astrocytosis) are performed. Active compounds would be expected to increase grip strength, reduce lipid peroxidase activity in the spinal cord, and reduce astrocytosis in the brain. Des1 inhibitors can also be administered in combination with other therapeutic agents for ALS, including riluzole and / or edabalon. The Des1 inhibitors disclosed herein would have disease-modifying activity in ALS or would be expected to provide symptom relief.

Measurement of activity in a model of impaired lipid accumulation:
A typical lipid accumulation disorder for which Des1 inhibitors may be expected to be effective is Faber's disease caused by the lack of activity of a lysosomal ceramide degrading enzyme known as acid ceramidedase (ASAH1). A mouse model in which ASAH1 is mutated (eg, P362R is an inactivation point mutation in the ASAH1 gene) is used to reproduce some key features of Faber's disease and to assess the potential efficacy of drug candidates. Acts as an readily available system. There is a characteristic massive accumulation of ceramide in tissues with elevated levels of various cytokines (eg, MCP1) detectable in the infiltration and circulation of the corresponding macrophages. Key assessments of potential Des1 inhibitor activity in this model are liver, spleen, kidney, and heart ceramide levels, spleen mass, plasma MCP1 levels, and liver and spleen tissue disease to assess macrophage infiltration. Including science. The Des1 inhibitor can be administered in combination with enzyme replacement therapy (eg, recombinant human acid ceramidase).

Measurement of in vivo activity in a model of congestive heart failure:
Des1 inhibitors, including those secondary to ischemia, would be expected to be effective in various types of congestive heart failure associated with diabetes, obesity, and lipotoxic cardiomyopathy. A representative and standard model in the industry is performed in mice examining the effect on the myocardium after occlusion of the coronary and / or ascending aorta. Briefly, in the case of ischemic-induced heart failure, after chest opening in C47BL / 6 mice, 9-0 prolen is placed around the left anterior descending coronary artery 2 mm below the left atrium to model myocardial infarction. Be ligated. Mice were then randomized to vehicle and treatment groups (using candidate Des1 inhibitors) for a total of 8 weeks (once or twice daily depending on the Des1 inhibitor used) and coronary arteries. It is initiated either before, at the same time, or after the occlusion. Treatment includes improvement of cardiac function (assessed by echocardiogram, including measures such as shortening rate and left ventricular end-diastolic diameter), as well as cardiac ceramide levels, inflammatory infiltrates (including macrophage infiltrates), and measures of cardiac apoptosis. It is expected to show improvement in endpoints assessed at takedown, including (including TUNEL staining) and / or cardiac remodeling due to fibrosis (including collagen levels). Treatment with Des1 inhibitors includes angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-adrenaline receptor blockers (including carvegilol), diuretics (including furosemide), and aldosterone antagonists. It is expected that co-administration with standard therapeutic agents, including (including eplerenone), inotropes (including millinone), guanylate cyclase inhibitors, and / or digoxins, may improve.

Measurement of in vivo activity in a model of diabetic nephropathy:
Des1 inhibitors are expected to be effective in the prevention or treatment of diabetic renal disease (DKD or nephropathy) and will therefore have efficacy in various animal models of DKD. The standard model relies on chemical damage to pancreatic β-cells (with streptozotocin, STZ) and induces hyperglycemia with consequent kidney damage. C57BL / 6 mice are randomized to vehicle and treatment groups and STZ is administered (IP at 200 mg / kg) to induce hyperglycemia and subsequent glomerular injury. Treatment can be initiated before, simultaneously with, or after STZ-induced renal injury for up to 4 weeks after STZ administration, including renal function (including glomerular filtration rate, BUN, and creatinine assessment), glomerular completeness. It would be expected to improve sex (albuminuria / proteinuria), and evidence of fibrosis (including collagen levels). In addition, treatment with Des1 inhibitors includes ACE inhibitors, ARBs, cholesterol-lowering agents (including statins and / or PCSK9 inhibitors), and agents that control calcium phosphate levels for bone health (including Severamar). It is expected that improvement can be achieved by concomitant administration with standard therapeutic agents including.

Measurement of in vivo activity in a model of acute renal injury:
Des1 inhibitors would be expected to be effective in the prevention or treatment of acute renal injury from a variety of etiologies, including ischemia / reperfusion and drug-induced (including chemotherapy and contrast media). The standard model of acute renal injury models cisplatin-related nephrotoxicity. C57BL / 6 mice were randomized to vehicle or treatment group and started 48 hours before or at the same time as intraperitoneal injection (25 mg / kg) of cisplatin injection (25 mg / kg), once daily for vehicle or treatment. Alternatively, two doses are continued for up to 72 hours after cisplatin injection. Treatment with Des1 inhibitors will reduce the increase in cisplatin-induced renal ceramide levels and improve renal function (assessed by blood BUN and / or creatinine levels and / or glomerular filtration rate). However, it is expected. It is also expected that treatment with Des1 inhibitors may be improved in combination with standard of care agents including N-acetylcysteine.

Measurement of in vivo activity in a sarcopenia model:
Des1 inhibitors will be expected to be effective in preserving muscle mass in the context of sarcopenia from a variety of causes, including aging, chronic kidney disease, malignancies, or chemotherapy. The standard model of cancerous sarcopenia-induced sarcopenia is as follows. On day 0, BALB / c mice are randomized and castrated into vehicle and treatment groups and 5 × 10 ⁵ C26 mouse cancer cells are transplanted into the flank. Mice are administered once or twice daily with either vehicle or treatment for 2 weeks starting on day 11 and are monitored every 3 days for tumor volume and body weight, as well as levator ani muscle weight at takedown. It is expected that treatment with Des1 inhibitors will retain skeletal muscle mass (eg, levator ani muscle mass) and / or body weight. Treatment with Des1 inhibitors includes testosterone, selective androgen receptor regulators, ghrelin agonists, myostatin antibodies, activin IIR antagonists, ACE inhibitors, beta antagonists, and fast skeletal muscle troponin activators. It is also expected that it can be improved by the combination of.

Other Embodiments The above detailed description is provided to assist one of ordinary skill in the art in implementing the present disclosure. However, the present disclosure described and claimed herein is scoped by the particular embodiments disclosed herein, as these embodiments are intended as illustrations of some embodiments of the present disclosure. Should not be limited. Any equivalent embodiment is intended to be within the scope of the present disclosure. In fact, various modifications of the present disclosure, in addition to those shown and described herein, will be apparent to those skilled in the art from the aforementioned description which does not deviate from the spirit or scope of the discovery of the present invention. .. It is also intended that such amendments are within the scope of the appended claims.

All US or foreign references, patents or applications cited in this application are incorporated herein by reference as if they were in their entirety as described herein. In the event of any inconsistency, what is literally disclosed herein supersedes.

Claims (78)

Compound of structural formula I:

Or its salt, in the formula,
L is from -C (= O)-, -S (= O) _2- , -NR ₃ S (= O) _2- , -NR ₃ C (= O)-, and -OC (= O)- Selected
W is selected from -NH- and -O-
R ¹ is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or 3 R ⁵ groups, or R ² is , Aryl and Heteroaryl, optionally substituted with 1, 2, or 3 ^R4 groups.
Whether R ³ is H or is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1, 2, or ³ R5 groups. , Or R ³ binds to R ¹ and the intervening N to form a heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R ⁵ groups.
At least one ^R4 may be hydroxy and the other (s) may be one or more other arbitrary substituents (s).
Each R ⁵ is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, And (heteroaryl) Heteroaryl, optionally substituted with 1, ² , or 3 R6 groups
A compound or salt thereof, each R ⁶ being independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy. 1 in claim 1, wherein L is selected from -S (= O) _2- , -NR ₃ S (= O) _2- , -NR ₃ C (= O)-, and -OC (= O)-. The compound described. The compound according to claim 2, wherein each R ⁴ is independently selected from cyano, halo, and hydroxy. The compound according to claim 3, wherein R ² is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazineyl and is substituted with one or two ^R4 groups. The compound according to claim 4, wherein R ² is substituted with R ⁴ groups at the para position from the binding point of W. R ² is

And
The compound according to claim 5, wherein X is selected from CH and N. The compound according to claim 6, wherein L is −NR ₃ C (= O) −. The compound according to claim 6, wherein L is −OC (= O) −. Has structural formula II

During the ceremony
W is selected from -NH- and -O-
X and Y are independently selected from CH and N,
R5 independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ⁽ aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, and (Heteroaryl) Selected from heteroaryl, optionally substituted with 1, ² , or 3 R6 groups.
Each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.
The compound or salt thereof according to claim 1, wherein n is selected from 1 and 2. The compound according to claim 9, wherein X is N. 10. The compound of claim 10, wherein R ⁵ is selected from aryls and heteroaryls and optionally substituted with one or ^two R6 groups. 11. The compound of claim 11, wherein each R ⁶ is independently selected from alkyl, halo, haloalkyl, and hydroxy. 12. The compound of claim 12, wherein R ⁵ is selected from phenyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups. 13. The compound of claim ¹³ , wherein each R6 is independently selected from halo and trifluoromethyl. The compound according to claim 14, wherein n is 1. The compound according to claim 15, wherein W is NH. The compound according to claim 16, wherein Y is N. 17. The compound of claim 17, wherein R ⁵ is selected from phenyl and pyridine-2-yl and optionally substituted with one or two R ⁶ groups. 18. The compound of claim ¹⁸ , wherein each R6 is independently selected from fluoro and trifluoromethyl. R5 is 2-fluorophenyl, ⁴ -fluorophenyl, 2,4-difluorophenyl, 4- (trifluoromethyl) phenyl, 4- (trifluoromethyl) pyridin-2-yl, 5- (trifluoromethyl). The compound according to claim 19, which is selected from pyridine-2-yl, 5-fluoropyridine-2-yl, and 3,5-difluoropyridine-2-yl. The compound according to claim 20, wherein R5 is 2,4 ^- difluorophenyl. Has structural formula III and

During the ceremony
X and Y are independently selected from CH and N,
R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ⁽ aryl) alkyl, (heteroaryl) alkyl, (aryl) aryl, (heteroaryl) aryl, (aryl) heteroaryl, and (heteroaryl). ) Selected from heteroaryl, optionally substituted with 1, 2, or ³ R6 groups,
Each R ⁶ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.
The compound or salt thereof according to claim 1, wherein n is selected from 1 and 2. 22. The compound of claim 22, wherein X is N. The compound according to claim 23, wherein Y is N. 24. The compound of claim 24, wherein each ^R6 is independently selected from halo and trifluoromethyl. 25. The compound of claim 25, wherein R5 is selected from phenyl, pyridinyl, ^pyridadinyl , pyrimidinyl, and pyrazinyl and optionally substituted with one or ^two R6 groups. 26. The compound of claim 26, wherein R5 is selected from phenyl and pyridine- ² -yl and optionally substituted with one or ^two R6 groups. 27. The compound of claim 27, wherein each ^R6 is independently selected from fluoro and chloro. R5 is ⁴ -fluorophenyl, 4-chlorophenyl, 4- (trifluoromethyl) phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 5-fluoropyridine-2-yl, and 5- (trifluoro). ) The compound of claim 28, selected from pyridine-2-yl.

The compound according to claim 1, which is selected from the above. The compound according to claim 1 or a salt thereof for use as a drug. The compound according to claim 1 or a salt thereof for use in the manufacture of a drug for the prevention or treatment of a Des1-mediated disease or condition. A pharmaceutical composition comprising the compound according to claim 1 or a salt, solvate, or prodrug thereof together with a pharmaceutically acceptable carrier. 33. The pharmaceutical composition of claim 33, which is formulated for oral administration. 33. The pharmaceutical composition of claim 33, further comprising another therapeutic agent. A method for inhibiting the activity of dihydroceramide desaturase (Des) in a biological sample, which comprises contacting the biological sample with the compound according to claim 1. A method of treating a Des1-mediated disorder in a subject in need thereof, comprising the step of administering the compound of claim 1 to the subject. 37. The method of claim 37, wherein the subject is a human. 37. The method of claim 37, wherein the Des1-mediated disorder is a metabolic disorder. The metabolic disorder is selected from metabolic syndrome, diabetes, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, alcoholic liver disease, non-alcoholic steatosis, obesity, and insulin resistance. The method according to claim 39. 37. The method of claim 37, wherein the Des1-mediated disorder is a lipid accumulation disorder. 41. The method of claim 41, wherein the lipid accumulation disorder is selected from Fabry's disease, Niemann-Pick's disease, Fabry's disease, Krabbe's disease, Gaucher's disease, Tay-Sachs disease, and allogeneic leukodystrophy. 37. The method of claim 37, wherein the Des1-mediated disorder is an autoimmune disease or a chronic inflammatory disease. The autoimmune disease or chronic inflammatory disease includes arthritis, polysclerosis, psoriasis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, scab, Graves' disease and Hashimoto's disease (chronic thyroiditis), tonic spondylitis, 43. The method of claim 43, which is also selected from cystic fibrosis. 37. The method of claim 37, wherein the Des1-mediated disorder is a cardiovascular disease. 45. The method of claim 45, wherein the cardiovascular disease is selected from atherosclerosis, hypertension, and cardiomyopathy. 37. The method of claim 37, wherein the Des1-mediated disorder is ischemia / reperfusion injury. The ischemic / reperfusion injury includes organ transplantation, acute renal injury, cardiopulmonary bypass, pulmonary hypertension, sickle erythema, myocardial infarction, stroke, surgical resection and reconstructive surgery, reattachment of appendages or other body parts, 47. The method of claim 47, which occurs in skin grafts or trauma. 37. The method of claim 37, wherein the Des1-mediated disorder is fibrosis or a related disease. The fibrosis or related diseases include pulmonary fibrosis, cystic fibrosis, liver fibrosis, liver cirrhosis, atrial fibrosis, endocardial myocardial fibrosis, joint fibrosis, myelodystrophy, glia scar, Peylony's disease, and progressive disease. 49. The method of claim 49, which is selected from massive fibrosis, dust pneumonia, retroperitoneal fibrosis, scleroderma, systemic sclerosis, abdominal adhesions, and adhesive arthritis. The method of claim 50, wherein the fibrosis or related disease is cystic fibrosis. 37. The method of claim 37, wherein the Des1-mediated disorder is cancer. The cancers are leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colon rectal cancer), rectal cancer, bladder cancer, lung cancer (non-small cell lung cancer, lung adenocarcinoma). , Lung flat epithelial cancer), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, bile sac cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer Head and neck squamous epithelial cancer (head and neck cancer), testis cancer, endocrine gland cancer, adrenal cancer, pituitary cancer, skin cancer, soft tissue cancer, vascular cancer Cancer, brain cancer, nerve cancer, eye cancer, medullary cancer, mesopharyngeal cancer, hypopharyngeal cancer, cervical cancer, and uterine cancer, nerve glue 52. The method of claim 52, which is selected from blastoma, medullary blastoma, stellate cell tumor, glioma, medullary carcinoma, gastrinoma, neuroblastoma, melanoma, myelodystrophy syndrome, and sarcoma. 52. The method of claim 52, wherein the method further comprises applying a non-chemical method of treating cancer. 54. The method of claim 54, wherein the method further comprises applying radiation therapy. 54. The method of claim 54, wherein the method further comprises performing surgery, thermal resection, focused ultrasound therapy, cryotherapy, or any combination thereof. 52. The method of claim 52, further comprising continuous or co-administration of a second therapeutic agent. The second therapeutic agent is selected from PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, CD47 inhibitor, indoleamine-2,3-dioxygenase inhibitor, and arginase inhibitor. , The method of claim 57. 58. The method of claim 58, wherein the PD-1 inhibitor is selected from pembrolizumab, pidirizumab, AMP-224, AMP-514, PDR001, and nivolumab. 58. The method of claim 58, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab. 58. The method of claim 58, wherein the CTLA-4 inhibitor is selected from ipilimumab. 58. The method of claim 58, wherein the CD47 inhibitor is selected from CV1, Hu5F9-G4, CC-90002, and TTI-621. 58. The method of claim 58, wherein the indoleamine-2,3-dioxygenase inhibitor is selected from 1-methyltryptophan, INCB024360, indoxymod, NLG919, norhalman, rosmarinic acid, epacadostat, and navoximod. 58. The method of claim 58, wherein the arginase inhibitor is selected from CB-1158 and norvaline. 58. The method of claim 57, wherein the second therapeutic agent is a DNA damaging agent. The DNA damaging agent is selected from ionizing radiation, radiation mimicking neocardinostatins, platinum acid salts, topo I inhibitors, topo II inhibitors, antimetabolites, alkylating agents, alkyl sulfonates, or antibiotics. , The method of claim 65. 65. The method of claim 65, wherein the chloroplatinate agent is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, robaplatin, tryplatin tetranitrate, picoplatin, satraplatin, prolinedac, and alloplatin. 65. The method of claim 65, wherein the topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan, and verotecan. 65. The method of claim 65, wherein the topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, sorbicin, and teniposide. The antimetabolites are aminopterin, methotrexate, pemetrexate, lartitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxalidine, cytarabine, gemcitabine, citarabine, gemcitabine. 65. The method of claim 65. The alkylating agent is chlormethine, cyclophosphamide, iposfamide, trophosphamide, chlorambucil, melphalan, predonimustine, bendamustine, uramstine, estramstine, carmustine, lomustine, semstin, fortemstin, nimustin, lanimustine, streptosocin, streptizin. 65. The method of claim 65, which is selected from nosulfan, treosulfane, carbocon, thiotepa, triaziquone, triethylenemelamine, procarbazine, dacarbazine, temozolomid, altretamine, mitbronitol, actinomycin, bleomycin, mitomycin, and plicamycin. .. 58. The method of claim 57, wherein the second therapeutic agent is a CHK1 inhibitor. 72. The method of claim 72, wherein the CHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01, and AZD7762. 58. The method of claim 57, wherein the second therapeutic agent is an antagonist monoclonal antibody (mAb). 17. The method of claim 74, wherein the antagonist mAb is selected from CTLA-4 mAb, PD-1 mAb, and PD-L1 mAb, CD47 mAb, and OX40 mAb. The compound according to claim 1, for use in human therapy. The compound according to claim 1, for use in the treatment of Des1-mediated diseases. Use of the compound according to claim 1 for the manufacture of a drug for treating a Des1-mediated disease.