WO2017150881A1 - Use of substituted n-(pyrrolidin-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine as janus kinase inhibitor - Google Patents

Abstract

Provided are substituted N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine and a composition for preventing hair loss or promoting hair regrowth, comprising the same

Description

Use of substituted N- (pyrrolidin-3-yl) -7H-pyrrolo [2,3-D] pyrimidin-4-amines as Janus kinase inhibitors

This invention is the result of the bio medical technology development project (No. 2014M3A9D9033717), which was carried out in cooperation with the Daegu Gyeongbuk New Drug Development Support Center with the support of the Korea Research Foundation as a fund of the Ministry of Science, ICT and Future Planning in 2016.

Substituted N- (pyrrolidin-3-yl) -7 H -pyrrolo [2,3- d ] pyrimidin-4-amine and its use as JAK inhibitors.

Janus kinase inhibitors (hereinafter referred to as "JAK") play a part in the various functions of tyrosine kinase in cellular proteins. A series of diverse actions occur through Signal Transducer and Activator of Transcription (collectively "STAT"), an important part of the starting point of cellular signaling systems initiated by cytokines.

JAK is widely involved throughout the mechanism of initiating cytokine expression. Four JAK proteins (JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2)) and seven STAT molecules are known as initiation factors. STAT is an intracellular transcription factor involved in cellular immunity, apoptosis, and the like. The mammalian STAT family includes seven members: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.

The JAK-STAT signaling pathway delivers information from extracellular chemical signals to the nucleus, resulting in DNA transcription and expression of genes involved in immunity and the like. The JAK-STAT system contains three main components: cell surface receptors, JAK and STAT proteins. Destroyed or dysregulated JAK-STAT functionality can lead to immunodeficiency and cancer.

All hairs go through a life cycle that includes three cycles: growth, anagen, catagen and telogen. The growth phase is the time when the hair is growing rapidly due to the active papilla cell division. The lifespan of the growing season varies depending on the type of hair, but for hair it is about 3-6 years. Growth hair accounts for 80-90% of the total hair, and hair loss is progressing in people with shorter growth periods and longer hair periods, resulting in a decrease in the proportion of growth hairs in all hairs. The degenerative phase is the end of the growth phase of the hair and the production of the hair gradually slows down, resulting in cell division and growth stopping. The degenerative lifespan is about 1-1.5 months and about 1% of the hair belongs to this stage. Resting phase is the final stage of growth when hair follicles and papillae are completely separated, causing hair follicles to atrophy and hair roots to rise upwards and hair fall out. The rest period lasts 3-4 months and 4-14% of all hairs fall into this phase. After the rest period, the activity of the nipple is active again, new nipples are created, and the hair in the resting period is pushed out of the scalp.

Cristiano (WO2012 / 061537) discloses a method for treating hair loss disorder in an individual by administering a Janus kinase / Signal Transducers and Activators of Transcription (JAK / STAT) inhibitor. It is disclosed that the JAK inhibitor is a JAK1 and / or JAK2 inhibitor, and the STAT inhibitor may be a STAT1 and / or STAT2 inhibitor. Cristiano (WO2013 / 149194A1) also discloses a method of treating alopecia disease in a subject by administering a JAK3 inhibitor. The JAK3 inhibitor may be tofacitinib.

One aspect provides a composition for preventing hair loss or promoting hair growth in a mammal, comprising a compound of Formula 1, or a pharmaceutically, cosmetically or pharmaceutically acceptable salt or solvate or stereoisomer thereof. to provide.

Another aspect provides a method of preventing hair loss or promoting hair growth of a subject, comprising administering the pharmaceutical composition to a mammalian subject.

One aspect is a compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof,

 (Formula 1)

And R ¹ is alkynyl wherein C _{1 -6} alkyl, C _{2 -6} alkenyl, or C _{2 -6} carbonyl,

R ² and R ³ together are - (C _{2 -6} alkyl) -, or form -, - (C _{2 -6} alkenyl)

R ⁴ is -W ¹ -R ⁶ ;

W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -, -S (= 0)-, or -S (= 0) _2- ;

R ⁵ is H or C _{1 -6} alkyl;

R ⁶ is H; Halo; CN; NO ₂ ; N ₃ ; C _{1 -10} alkyl: C _{2 -10} alkenyl; _-10 C ₂ alkynyl; C _{1 -6} haloalkyl; C _{1 -10} alkyl, C _{1 -6} haloalkyl, halo, CN, NO _2, and -O- (C _{1 -10} alkyl) optionally substituted with one or more substituents selected from the group consisting of, C _{5 -20} aryl ; C _{3 -7-cycloalkyl;} -C (C = O) heterocycloalkyl having from 3 to 7 ring atoms optionally substituted with (C _{1 -6} alkyl); Heteroaryl having 3 to 7 ring atoms; 3 to 7 ring atoms, heteroaryl of the - (C _{1 -10} alkyl); - (C _{1 -10} alkyl) -CN; - (C _{1 -10} alkyl) -N _3; - (C _{1 -10} alkyl) -O- (C _1-6 alkyl); - (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; Or - together are (C _{1 -10} alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b , or independently represent H or C _{1 -6} alkyl that is containing the compound, or a pharmaceutically his drug, acceptable cosmetic chemical or food chemical salt or solvate or stereoisomer of formula (I) as an active ingredient, hair loss in a mammal To prevent or promote hair growth or hair growth.

In the present invention, R ¹ of the compound of formula (I) is formula (1) may be a straight or branched C _1-6 alkyl, for, example, a straight or branched C _{1 -3} alkyl. The C _{1 -6} alkyl is for example, a neopentyl, or hexyl silil methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter- butyl, pentyl,. The compounds of formula (I) is of formula (1) R ¹ is also straight or branched C _{2 -6} alkenyl, for example, it may be an alkenyl C _{2 -3} al. The compounds of formula (I) is of formula (1) R ¹ is also straight or branched C _{2 -6-alkynyl,} for example, C _{2 -3} may be an alkynyl group.

In the present invention, R ² and R ³ are together - may be to form a - (C _{2 -6} straight or branched alkyl). R ² and R ³ may be together to form — (CH ₂ ) _n −, where n is 2 to 6, for example. In addition, R ² and R ³ are together - may be to form a - (C _{2 -6} alkenyl straight or branched al).

In the present invention, W ¹ has no corresponding atom, or is -C (= 0)-, -C (= S)-, -C (= 0) O-, -C (= 0) NR ^5- , -C ( = S) NR ^5- , or -S (= 0) _2- .

In the present invention, R ⁶ is C _{1 -10} alkyl (for example, C _{1 -6} alkyl); C _{2 -10} alkenyl (e.g., C _{2 -6} alkenyl); C _{2 -10} alkynyl (e.g., C _{2 -6-alkynyl);} C _{1 -6} haloalkyl (for example, C _{1 -3} haloalkyl); C _{1 -10} alkyl (for example, C _{1 -6} alkyl), C _{1 -6} haloalkyl (for example, C _{1 -3} haloalkyl), halo, CN, NO _2, and -O- (C _{1 -10} alkyl) (such as, -O- (C _{1 -6} alkyl)) optionally substituted with one or more substituents selected from the group consisting of, C _{5 -20} aryl group (e.g., C _{6 -12} aryl group); C _{3 -7-cycloalkyl;} -C (C = O) heterocycloalkyl having from 3 to 7 ring atoms optionally substituted with (C _{1 -6} alkyl) (for example, piperidinyl); Heteroaryl having 3 to 7 ring atoms (eg, furanyl, pyridinyl, or imidazolyl); 3 to 7-heteroaryl (e. G., Furanyl, pyridinyl, or imidazolyl) having a ring atom - (C _{1 -10} alkyl); - (C _{1 -10} alkyl) -CN; - (C _{1 -10} alkyl) -N _3; - (C _{1 -10} alkyl) -O- (C _{1 -6} alkyl); (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; Or - together are (C _{1 -10} alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b , or independently is H or C _{1 -6} alkyl. R ⁶ is, for example, C _{1 -6} alkyl; C _{2 -6} alkenyl; C _{2 -6-alkynyl;} C _{1 -3} alkyl, halo (for example, C _{1 -3} triple ruro O-alkyl); C _{1 -6} alkyl, C _{1 -3} alkyl, halo (for example, C _{1 -3} triple ruro O-alkyl), halo, CN, at least one selected from the group consisting of NO _2, and -O- (C _{1 -6} alkyl) optionally substituted with a substituent, C _{6 -12} aryl group (e.g., phenyl, naphthalenyl, or biphenyl); C _{3 -7-cycloalkyl} (e.g., cyclopropyl, or cyclohexyl); -C (C = O) heterocycloalkyl having from 3 to 7 ring atoms optionally substituted with (C _{1 -6} alkyl) (for example, piperidinyl); Heteroaryl having 3 to 7 ring atoms (eg, furanyl, pyridinyl, or imidazolyl); 3 to 7 ring atoms, heteroaryl of the - (C _{1 -6} alkyl) (for example, furanyl - (C _{1 -6} alkyl), pyridinyl - (C _{1 -6} alkyl), imidazolyl or - (C _1-6 alkyl)); - (C _{1 -6} alkyl) -CN; - (C _{1 -6} alkyl) -N _3; - (C _{1 -6} alkyl) -O- (C _1-3 alkyl); (C _{1 -6} ^{alkyl) -C (= O) NR a} R b; Or - together are a (C _{1 -6} alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d - (C _{1 -6} ^{alkyl) -NR a C (= O)} R b , or independently is H or C _{1 -3} alkyl.

In the present invention, one embodiment of the compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof,

And of formula (1) R ¹ is C _{1 -6} alkyl,

R ² and R ³ can together form -, - (C _{2 -6} alkyl)

R ⁴ is -W ¹ -R ⁶ ;

W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -Or -S (= 0) _2- ;

R ⁵ is H or C _{1 -6} alkyl;

R ⁶ is C _{1 -10} alkyl; C _{1 -6} haloalkyl; C _{1 -10} alkyl, C _{1 -6} haloalkyl, halo, CN, NO _2, and -O- (C _{1 -10} alkyl) optionally substituted with one or more substituents selected from the group consisting of, C _{5 -20} aryl ; C _{3 -7-cycloalkyl;} -C (C = O) heterocycloalkyl having from 3 to 7 ring atoms optionally substituted with (C _{1 -6} alkyl); Heteroaryl having 3 to 7 ring atoms; 3 to 7 ring atoms, heteroaryl of the - (C _{1 -10} alkyl); - (C _{1 -10} alkyl) -CN; -( _{Ci_ 10} alkyl) -N ₃ ; - (C _{1 -10} alkyl) -O- (C _{1 -6} alkyl); (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b; or - a (C _{1 -10} alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d are each independently is H or C _{1 -6} alkyl. In the present invention, examples of the compound of Formula 1 R ¹ is C _{1 -6} alkyl, R ² and R ³ together are - (C _{2 -6} alkyl) - and the form, W ¹ is -C (= O) - and, R ⁶ is--CN in compound (C _{1 -5-alkyl)} - (C _{1 -10} alkyl) -CN, or.

In the present invention, another embodiment of the compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof,

R ¹ in formula 1 is methyl,

R ² and R ³ together form -CH ₂ CH _2- ,

R ⁴ is -W ¹ -R ⁶ ;

W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -Or -S (= 0) _2- ;

R ⁵ is H or C _{1 -6} alkyl;

R ⁶ is C _{1 -10} alkyl; C _{1 -6} haloalkyl; C _{1 -10} alkyl, C _{1 -6} haloalkyl, halo, CN, NO _2, and -O- (C _{1 -10} alkyl) optionally substituted with one or more substituents selected from the group consisting of, C _{5 -20} aryl ; C _{3 -7-cycloalkyl;} -C (C = O) heterocycloalkyl having from 3 to 7 ring atoms optionally substituted with (C _{1 -6} alkyl); Heteroaryl having 3 to 7 ring atoms; 3 to 7 heteroaryl -C _{1 -10} alkyl having ring atoms; - (C _{1 -10} alkyl) -CN; -( _{Ci_ 10} alkyl) -N ₃ ; - (C _{1 -10} alkyl) -O- (C _{1 -6} alkyl); (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b; - and the (C _{1 -10} alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d is independently H or a C _{1 -6} alkyl each other.

In the present invention, another embodiment of the compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof,

R ¹ in formula 1 is methyl,

R ² and R ³ together form -CH ₂ CH _2- ,

R ⁴ is -W ¹ -R ⁶ ;

W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -Or -S (= 0) _2- ;

R ⁵ is H or C _{1 -6} alkyl;

R ⁶ is C _{1 -10} alkyl; Trifluoroacetate - (C _{1 -3} alkyl); A C _{1 -10} alkyl, trifluoromethyl-optionally substituted with one or more substituents selected from the group consisting of (C _{1 -3} alkyl), halo, CN, NO _2, and -O- (C _{1 -10} alkyl), Phenyl or naphthalenyl or biphenyl; C _{3 -7-cycloalkyl;} To the -C (C = O) (C 1 -6 alkyl), optionally substituted, piperidinyl or morpholinyl; Furanyl; Pyridinyl; Imidazolyl - (C _{1 -10} alkyl); - (C _{1 -10} alkylene) -CN; - (C _{1 -10} alkyl) -N _3; - (C _{1 -10} alkyl) -O- (C _{1 -6} alkyl); (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b; Or - a (C _1-10 alkyl) -NR ^c R ^d, wherein ^{R a, R b, R c} , and R ^d is independently of each other H or a C _{1 -6} alkyl.

In the present invention, another embodiment of the compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof has the general formula of Formula 2,

(Formula 2)

R ⁴ in Formula 2 is -W ¹ -R ⁶ ;

W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -Or -S (= 0) _2- ;

R ⁵ is H or C _{1 -6} alkyl;

R ⁶ is

And W ¹ in this case is not the atom, C _{1 -10} alkyl,

W ¹ is -C (= O) - when, C _{1 -10} alkyl; C _{3 -7-cycloalkyl;} - (C _{1 -10} alkyl) -CN; - (C _{1 -10} alkyl) -N _3; R ^a and R ^b are independently H or C _{1 -6} alkyl, each - (C _{1 -10} ^{alkyl) -NR a C (= O)} R b; R ^a and R ^b are each independently H or C _{1 -6} alkyl, - (C _{1 -10} ^{alkyl) -C (= O) NR a} R b; Phenyl; Phenyl substituted with one or more substituents selected from the group consisting of -CF ₃ and CN; Piperidinyl substituted by -C (C = O) (C 1 -6 alkyl); Furanyl; Pyridinyl; Imidazolyl - (C _{1 -10} alkyl); - (C _{1 -10} alkyl) -O- (C _{1 -6} alkyl); Or R ^c and R ^d are independently H or C _{1 -6} alkyl, each - (C _{1 -10} alkyl) -NR ^c R ^d ego,

And the (C _{1 -10} alkyl) -CN, - W ¹ is -C (= S) - when,

And the (C _{1 -10} alkyl), - W ¹ is -C (= O) O- case,

If W ¹ is ^{-C (= O) NR 5,} - (C 1 -10 alkyl); C _{3 -7-cycloalkyl;} Phenyl; Halo, and C _{1 -10} is phenyl substituted with one or more substituents selected from the group consisting of alkyl; Biphenyl; Is halo or C _{1 -10} and the biphenyl is substituted by one or more substituents selected from the group consisting of alkyl,

When W ¹ is -C (= S) NR ⁵ , it is phenyl substituted with one or more -CF ₃ ,

W ¹ is -S (= O) ₂ - when, - (C _{1 -10} alkyl); -CF ₃ ; Piperidinyl; Morpholinyl; R ^c and R ^d are independently H or C _{1 -6} alkyl, each - (C _{1 -10} alkyl) -NR ^c R ^d; Phenyl; - (C _{1 -10} alkyl), -O- (C _{1-6 alkyl), -CF 3, NO 2,} CN, halo and phenyl substituted with one or more substituents independently selected from; Naphthalenyl; - (C _{1 -10} alkyl), -O- (C _{1 -6} alkyl), - (C _{1 -6} haloalkyl), NO _2, CN, and naphthalenyl optionally substituted with one or more halo substituents independently selected to be. In the present invention, examples of the compound of Formula 2 is W ¹ is -C (= O) -, and, R ⁶ is - (C _{1 -10} alkyl) -CN, or - (C _{1 -5} alkyl) -CN Phosphorus compound.

In the present invention, the compound of formula 1 may be in the form of a pharmaceutically, cosmetically or food acceptable salt thereof. The salts are salts derived from conventional acid addition salts used in the field of JAK inhibitors, such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid. Salts derived from organic acids such as citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid Include. The salts also include salts derived from conventional metal salt forms, such as metals such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salts or metal salts may be prepared according to conventional methods.

In the present invention, the compound of formula 1 may also be in the form of solvates thereof. "Solvate" means a complex or aggregate formed by one or more solute molecules, i.e., a compound of Formula 1 or a pharmaceutically, cosmetically or food acceptable salt thereof, and one or more solvent molecules. Solvates can be complexes or aggregates formed with, for example, water, methanol, ethanol, isopropanol or acetic acid.

In the present invention, the compound of formula 1 may also be in the form of its stereoisomers. The stereoisomers include all stereoisomers such as enantiomers and diastereomers. The compound may be a stereoisomerically pure form of a stereoisomer or a mixture of one or more stereoisomers, for example a racemic mixture. Separation of certain stereoisomers may be carried out by one of the conventional methods known in the art. In the present invention, some examples of the compound of the formula (1) may have a greater JAK inhibitory effect of certain stereoisomers, such as 3 to 40 times greater than the racemic mixture. In this case, the dosage can be reduced by using specific stereoisomers. For example, the compound of Example 5 having an R-batch (IC ₅₀ value = 8.5 nM) is about 3.5 times higher JAK1 inhibition compared to the compound of Example 55 which is its racemic mixture (IC ₅₀ value = 29.3 nM) Has activity. Therefore, by separating certain stereoisomers, such as enantiomers or diastereomers, which have a large inhibitory effect on JAK, it is possible to efficiently treat diseases associated with JAK, such as hair loss diseases.

Compound of Formula 1 is

(R) - N - (5- butyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine;

( R ) -N -methyl- N- (5-pentyl-5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidin-4-amine;

(R) -2- methyl-1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl Propan-1-one;

(R) -2- azido-1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5 I) ethan-1-one;

(R) -3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3- Oxopropanenitrile;

(R) -3- methyl-1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl ) Butan-1-one;

(R) - N - (2- (7- ( methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl) acetamide;

(R) - N - methyl-3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl ) -3-oxopropanamide;

(R) - cyclopropyl (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -methanone;

(R) -1- (4- (7- ( methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl ) Piperidin-1-yl) ethan-1-one;

(R) - furan-2-one (7 (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) Methanone;

(R) - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-3- I) methanone;

(R) - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (phenyl) methanone ;

(R) - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-4 I) methanone;

(R) -3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) -benzonitrile ;

(R) -4- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) -benzonitrile ;

(R) - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (2- (tri Fluoromethyl) phenyl) methanone;

(R) - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (3- (tri Fluoromethyl) phenyl) methanone;

(R) -3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3- Thioxopropanenitrile;

Isobutyl (R) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate;

(R) - N - butyl-7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide;

(R) - N - cyclohexyl-7 (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxamide ;

(R) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) - N - phenyl-5-azaspiro [2.4] heptan-5-carboxamide;

(R) - N - (4-fluorophenyl) -7- (methyl (7 H-pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane- 5-carboxamide;

(R) - N - (2,4- dichloro-phenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide;

(R) - N - (3,4- dichloro-phenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide;

(R) - N - (2,5- dichloro-phenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide;

(R) - N - (2,3- dichloro-phenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide;

(R) - N - (3- chloro-4-methylphenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] Heptane-5-carboxamide;

(R) - N - ([ 1,1'- biphenyl] -2-yl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5 Azaspiro [2.4] heptan-5-carboxamide;

(R) - N - (3,5- bis (trifluoromethyl) phenyl) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5- Azaspiro [2.4] heptan-5-carbothioamide;

( R ) -N -methyl- N- (5-((trifluoromethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

(R) - N - (5- ( ethyl-sulfonyl) -5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin-4 Amines;

(R) - N - (5- ( isopropyl-sulfonyl) -5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin -4 Amines;

( R ) -N -methyl- N- (5- (propylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine-4- Amines;

( R ) -N -methyl- N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine-4- Amines;

( R ) -N- (5-((2-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N- (5-((3-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N- (5-((4-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

(R) -2 - ((7- ( methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl ) Benzonitrile;

(R) -3 - ((7- ( methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl ) Benzonitrile;

(R) -4 - ((7- ( methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl ) Benzonitrile;

( R ) -N -methyl- N- (5-((2-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N -methyl- N- (5-((3-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N -methyl- N- (5-((4-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N -methyl- N- (5- (m-tolylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine- 4-amine;

( R ) -N- (5-((4-methoxyphenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N -methyl- N- (5-((4- (trifluoromethyl) phenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2 , 3- d ] pyrimidin-4-amine;

(R) - N - methyl - N - (5- (naphthalene-2-sulfonyl some accounts) -5-azaspiro [2.4] heptan-7-yl) -7 H - pyrrolo [2,3- d] pyrimidine -4-amine;

( R ) -N -methyl- N- (5- (piperidin-1-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] Pyrimidin-4-amine;

( R ) -N -methyl- N- (5- (morpholinosulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine-4 Amines;

1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one;

2-methoxy-1 (7- (methyl (7 H-pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane- 1-one;

2-azido-1- (7- (methyl (7 H-pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane- 1-one;

3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxo-propanenitrile;

N - (2- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2 Ethyl) acetamide;

N - methyl-3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3- Oxopropanamide;

3-Amino-1 - (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan -1 -On;

2- (1 H - imidazol-1-yl) -1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4 ] Heptan-5-yl) ethan-1-one;

3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxo-propanenitrile ;

Isobutyl-7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate;

N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] pyrimidin-4-amine;

N- (5-((2-aminoethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] pyrimidine-4 Amines;

(S) -1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan -1 -On;

(S) -2- azido-1- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5 I) ethan-1-one;

(S) -3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3- Oxopropanenitrile;

(S) - N - methyl-3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl ) -3-oxopropanamide;

(S) -4- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carbonyl) -benzonitrile ;

(S) -3- (7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3- Thioxopropanenitrile;

Isobutyl (S) -7- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane-5-carboxylate;

(S) - N - (5- ( ethyl-sulfonyl) -5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin-4 Amines;

( S ) -N -methyl- N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine-4- Amines;

(R) - N - (5- ethyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin-4-amine;

(R) -3- (8- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -6-azaspiro [3.4] octane-6-yl) -3- Oxopropanenitrile; or

(S) -3- (8- (methyl (7 H - pyrrolo [2,3- d] pyrimidin-4-yl) amino) -6-azaspiro [3.4] octane-6-yl) -3- Oxopropanenitrile.

In the present specification, unless otherwise indicated, the following terms have the following meanings.

The term "alkyl" refers to a straight or branched monovalent saturated hydrocarbon group. Unless defined otherwise, the alkyl groups generally comprise 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, and t-butyl), pentyl (eg n-pentyl, isopentyl, and neo Pentyl), n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group having one or more carbon-carbon double bonds, straight or branched. Unless defined otherwise, the alkenyl groups generally comprise 2 to 10, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Alkenyl groups include, for example, ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, cyclohexenyl, n-hex-3-enyl and the like.

The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group having one or more carbon-carbon triple bonds, linear or branched. Unless defined otherwise, the alkynyl groups generally comprise 2 to 10, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Alkynyl groups include, for example, ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

The term "haloalkyl" means an alkyl group having one or more halogen substituents. Haloalkyl includes -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CCl ₃ , -CHCl ₂ , and -C ₂ Cl ₅ . Unless defined otherwise, the haloalkyl groups generally contain 1-6, 1-4 or 1-3 carbon atoms.

The term "aryl" means an aromatic hydrocarbon group having a monocyclic or polycyclic ring. The polycyclic may include those having a fused ring (eg, naphthalene) and / or having an unfused ring (eg, biphenyl). The polycyclic ring may be, for example, having two, three or four rings. Unless defined otherwise, the aryl groups generally have 5 to 20, 6 to 15, 6 to 12, or 6 to 10 carbon ring atoms. Such aryl groups include, for example, phenyl, naphthalenyl (eg, naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, phenanthrenyl and the like.

The term "cycloalkyl" denotes a non-aromatic carbocycle comprising cyclized alkyl, alkenyl and alkynyl groups. The cycloalkyl group may include a monocyclic or polycyclic ring. The polycyclic ring is, for example, having two, three or four fused rings. Unless defined otherwise, the cycloalkyl groups generally comprise 3 to 10, or 3 to 7 ring carbon atoms. The cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcarnyl, adamantyl, and the like. Include.

The term "heterocycloalkyl" means a nonaromatic heterocycle comprising heteroatoms that form a ring as one or more atoms selected from N, O, or S. Heterocycloalkyl groups include monocyclic or polycyclic structures, for example, structures having two, three or four fused rings. Examples of “heterocycloalkyl” groups include morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxol, benzo -1,4-dioxane, piperidinyl, pyrrolidinyl, isoxoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl and the like. Unless defined otherwise, the heterocycloalkyl group includes atoms that form 3 to 10, 3 to 7, 5 to 7, or 5 to 6 rings.

The term "heteroaryl" means a monovalent aromatic group having at least one hetero atom selected from N, O and S as ring members. Heteroaryl groups include monocyclic or polycyclic structures. The polycyclic ring may be, for example, having two, three or four condensed rings. Unless defined otherwise, the heteroaryl groups generally comprise 3 to 10, 3 to 7, or 3 to 5 ring atoms. The heteroaryl group may include one, two or three heteroatoms. Heteroaryl groups are, for example, pyridyl, N -oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imida Zolyl, furanyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 , 2,4-thiadiazolyl, isothiazolyl, benzothienyl, furinyl, benzimidazolyl, indolinyl and the like.

The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

The term "arylalkyl" denotes an alkyl group substituted by an aryl group. "Aryl" and "alkyl" are as defined above.

The term "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group. "Heteroaryl" and "alkyl" are as defined above.

The composition may comprise a pharmaceutically, cosmetically or food acceptable carrier.

In the above composition, "pharmaceutically, cosmetically or food acceptable carrier" refers to a substance used in combination with the active ingredient, generally an inert substance, to assist in the application of the active ingredient. The carrier comprises conventional pharmaceutically, cosmetically or food acceptable acceptable excipients, additives or diluents. The carrier is for example a filler, a binder, a disintergrant, a buffer, a preservative, an antioxidant, a lubricant, a flavor, a thickener, a coloring agent, an emulsifier, a suspension It may be one or more selected from agents, stabilizers, and isotonic agents.

The compositions of the present invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical. Thus, the compositions of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of oral tablets, excipients such as lactose, corn starch and the like and glidants such as magnesium stearate may usually be added. For oral capsules, lactose and / or dry corn starch may be used as diluent. If an oral aqueous suspension is required, the active ingredient may be combined with an emulsifier and / or suspending agent. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared and the pH of the solution must be properly adjusted and buffered. For intravenous administration, the total concentration of the solute should be adjusted to give isotonicity to the formulation. The composition according to the invention may be in the form of an aqueous solution comprising a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular blood flow by local bolus injection. The composition may be in a formulation for topical application. For example, the composition may be a formulation for application to the skin, including the scalp. The composition may be a cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma formulation.

The composition of the compound of Formula 1 is once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, eight times per week, whole body per week, 10 per week It may have a formulation for administration once, 11 times a week, 12 times a week, 13 times a week or 14 times a week.

Compounds of Formula 1 as defined in the present invention may exhibit an effect of inhibiting one or more JAK activities. "Inhibition" herein includes reducing the activity of one or more kinase.

As used herein, "JAK" includes all enzymes of the Janus kinase family. Compounds of some embodiments of the invention inhibit the activity of one or more of JAK1, JAK2, JAK3 and TYK2. In some embodiments of the invention, the compound of formula 1 selectively inhibits the activity of JAK1, JAK2 and TYK2. On the other hand, in some other embodiments, the compound of formula 1 selectively inhibits JAK1 alone. For example, the compound of Example 44 inhibits the activity of JAK1, JAK2, JAK3 and TYK2. Specifically, the compound of Example 44 inhibits the activity of JAK1, JAK2, JAK3 and TYK2 in the presence of 1 uM, respectively, by 100%, 96%, 96% and 98%. In addition, the compounds of Example 39 selectively inhibit the activity of JAK1, JAK2, and TYK2. Specifically, the compound of Example 39 inhibits the activities of JAK1, JAK2, and TYK2 in the presence of 1 uM by 99%, 95%, and 93%, respectively, while JAK3 inhibits only 65%. In addition, the compound of Example 60 selectively inhibits the activity of JAK1. Specifically, the compound of Example 60 inhibits -3%, -14%, and 0% of the activities of JAK2, JAK3, and TYK2, respectively, in the presence of 1 uM, while JAK1 inhibits 96%. Here, the inhibitory effect is a measure of the extent to which JAK inhibits the conversion of ATP to ADP in the presence of the compound. When the measured absorbance value is lower than the standard absorbance curve, the inhibitory effect has a negative value. This is measured below the negative control value, which is substantially equal to 0% showing no inhibitory efficacy.

The compounds described herein may be selective for certain JAK types. The term “selective” is used herein when a compound exhibits higher regulatory activity on a particular JAK than at least one JAK. Some embodiments are inhibitors selective for JAK1 or JAK2 over JAK3 or TYK2. Another embodiment is an inhibitor selective for JAK1 over JAK2, JAK3, and / or TYK2. In particular, since JAK3 inhibitors may exhibit immunosuppressive effects, inhibitors selective to JAK2 compared to JAK3 can be used to treat cancers such as multiple myeloma or myeloid fibrosis without immunosuppressive side effects. Selectivity can be at least 5 times, 10 times, 20 times, 40 times, 100 times, 200 times, 500 times and 1000 times. Compared with% inhibition at 1 uM, the compounds of some embodiments may have 44-fold selectivity in JAK1 over JAK2 (-91 <JAK1 (%) / JAK2 (%) <44). In addition, the compounds of some embodiments may be those that have 40-fold selectivity in JAK1 relative to JAK3 (-65 <JAK1 (%) / JAK3 (%) <40). In addition, the compounds of some embodiments may be one that has 62-fold selectivity in JAK1 relative to TYK2 (-19.75 <JAK1 (%) / TYK2 (%) <62). Selectivity can be measured by techniques known in the art in the art. In some embodiments the selectivity can be tested at Km of each enzyme.

The compositions of the present invention can be combined with other compounds to prevent hair loss in mammals or to promote hair growth. The other compound may be fludarabine, epicalocatechin-3-gallate, hyperporin, or tofacitinib. Combination therapy can produce a synergistic effect. Agents for combination therapy may be combined with a JAK inhibitor in a single or continuous dosage form, or may be administered simultaneously or sequentially in separate dosage forms.

Cristiano (WO2012 / 061537) discloses a method for treating hair loss disorder in an individual by administering a Janus kinase / Signal Transducers and Activators of Transcription (JAK / STAT) inhibitor. It is disclosed that the JAK inhibitor is a JAK1 and / or JAK2 inhibitor, and the STAT inhibitor may be a STAT1 and / or STAT2 inhibitor. Cristiano (WO2013 / 149194A1) also discloses a method of treating alopecia disease in a subject by administering a JAK3 inhibitor. The JAK3 inhibitor may be tofacitinib. Thus, the compound of formula 1, which is a JAK / STAT inhibitor, has the activity of preventing hair loss or promoting hair growth in mammals.

In the composition, the compound of Formula 1 may be to inhibit JAK-STAT signaling. The compound of formula 1 may be, for example, inhibiting JAK1, JAK2, JAK3, STAT1, STAT2, STAT3, STAT4, STAT5, or STAT6.

The composition may be a pharmaceutical, cosmetic, or food composition.

The composition may be for treating alopecia. The alopecia is alopecia areata, androgenetic alopecia, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, circumscribed alopecia, congenital alopecia. (alopecia congenitalis), alopecia pubis, alopecia seborrheica, alopecia senilis, alopecia totalis, alopecia universalis, alopecia hair loss (anagen effluvium) telogen effluvium, stress alopecia, female pattern alopecia, or male pattern alopecia.

The composition may be a cosmetic composition. The composition includes hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nourishment cream, hair moisturizer cream, hair massage cream, hair wax, hair aerosol, Hair Pack, Hair Nutrition Pack, Hair Soap, Hair Cleansing Foam, Hair Oil, Hair Dryer, Hair Preservative, Hair Dye, Hair Wave, Hair Bleach, Hair Gel, Hair Glaze, Hair Dresser, Hair Lacquer, Hair Moisturizer, Hair It may be a formulation of a mousse, eyebrow nutrient, eyelash nutrient or hairspray.

In the composition, the mammal may be a human.

Another aspect provides a method of preventing hair loss or promoting hair growth in a subject, comprising administering to the mammalian subject a compound of Formula 1, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. . The compound of the formula (1) is as described above. The compound of formula 1, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, may be in the form of a composition as described above.

The administration may be to administer a therapeutically effective amount.

In this method, a person skilled in the art can appropriately select the route of administration upon administration according to the condition of the patient. The administration can be oral, parenteral, or topical administration.

In this method, the dosage will vary depending on various factors such as the patient's condition, route of administration, judgment of the attending physician, and the like as described above. Effective dosages can be estimated from dose-response curves obtained in vitro or in animal model tests. The proportions and concentrations of the compounds of the present invention in the compositions to be administered may be determined by chemical properties, route of administration, therapeutic dosage, and the like. The dosage may be administered to an individual in an effective amount of about 1 μg / kg to about 1 g / kg per day, or about 0.1 mg / kg to about 500 mg / kg per day. The dose may vary depending on the age, weight, sensitivity, or symptoms of the individual.

In the method, the disease may be a disease associated with increased JAK activity.

The compound of formula 1 to be administered further comprises the step of determining whether the hair growth of the subject compared to the hair growth of the subject before treatment with the compound of formula 1 in the subject suffering from alopecia. In one embodiment, the administration is subcutaneous, intramuscular, intraperitoneal or intravenous injection; Injection; Oral, nasal or topical delivery; Or combinations thereof. In some embodiments, the administration is daily, weekly, every two weeks, monthly, every two months, or yearly. In some embodiments, the compound of formula 1 is once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, eight times per week, nine times per week, ten times per week , 11 times per week, 12 times per week, 13 times per week, or 14 times per week. In other embodiments, the subject receives a compound of Formula 1 for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks or at least 16 weeks. . In some embodiments, the method further comprises administering another JAK1 / 2 inhibitor to the subject. In further embodiments, the administration of the JAK1 / 2 inhibitor is performed simultaneously with the administration of the compound of Formula 1. In still other embodiments, the administration of the JAK1 / 2 inhibitor is performed sequentially in any order with the administration of the compound of Formula 1. In some embodiments, the JAK1 / 2 inhibitor is INCB 018424, GLPG0634, AG490, CYT387, SB1518, LY3009104 (Baricitinib; INCB28050), AZD1480, TG101348, BMS-911543 or CEP-701.

In the present invention, the compound of formula 1, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof may be prepared by the preparation method according to Scheme 1 below.

(Scheme 1)

In Scheme 1, L ¹ and L ² in Formulas 3, 4, 5, 6, 7, and 8 each represent a leaving group, Pr ¹ and Pr ² represent an amino-protecting group, X is F, Cl, Br, or I, and R ¹ , R ² , R ³ , and R ⁴ are as defined in formula (1).

The method comprises the steps of (a) reacting a compound of Formula 3 or a salt thereof with a compound of R ¹ -X ¹ to produce a compound of Formula 4; And reacting the compound of Formula 4 with 6-halo-7-deazapurin to produce the compound of Formula 6; Or (b) reacting the compound of Formula 3 or a salt thereof with 6-halo-7-deazapurin to produce a compound of Formula 5; And reacting the compound of Formula 5 with the compound of R ¹ -X ¹ to produce the compound of Formula 6; (c) deprotecting the nitrogen of the pyrrolidine ring of the compound of formula 6 to produce a compound of formula 7; (d) reacting the compound of Formula 7 with R ⁴ -X ² to produce a compound of Formula 8; And (e) deprotecting the compound of Formula 8 to produce the compound of Formula 1.

In the above method, (a) "reacting a compound of formula 3 or a salt thereof with a compound of R ¹ -X ¹ to produce a compound of formula 4" and "compound of formula 5 and R ¹ -X ¹ Reacting with the compound to produce the compound of formula 6 " includes alkylation (eg, methylation), alkenylation, or alkynylation.

In the above method, (a) "reacting a compound of formula 4 with 6-halo-7-deazapurin to produce a compound of formula 6" and "compound of formula 3 or a salt thereof 6-halo- The step of reacting with 7-deazapurin to produce the compound of formula 5 " can be carried out while heating under appropriate solvent or under reflux conditions. The 6-halo-7-deazapurin can be purchased commercially. The halo can be for example chloro.

In the method, (c) "deprotecting the nitrogen of the pyrrolidine ring of the compound of formula 6 to produce a compound of formula 7"; And (e) “deprotecting the compound of Formula 8 to produce the compound of Formula 1” can be performed by any known deprotection method.

In addition, in the above method, (d) "reacting a compound of Formula 7 with R ⁴ -X ² to generate a compound of Formula 8" may be performed by substitution of X ² by N.

In this method, the term “leaving group” means a functional group or atom that can be replaced by another functional group or atom in a substitution reaction, eg, a nucleophilic substitution reaction. For example, representative leaving groups include chloro, bromo and iodine groups; Sulfonic ester groups such as tosylate, brosylate and nosylate and the like; And alkyloxy groups such as acetoxy and trifluoroacetoxy and the like.

The term "protected" means that one or more functional groups of the compound are protected from unwanted reactions using protecting or blocking groups. Functional groups that can be protected include, for example, carbamates (such as tert-butoxycarbonyl), which are representative protecting groups for amino groups.

The term "amino-protecting group" means a protecting group suitable for preventing unwanted reactions in amino groups. Representative amino-protecting groups are tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.

In the present invention, the compound of formula (1) by reacting a compound of formula (9) or a salt thereof with a compound of R ⁴ -L ² to produce a compound of formula (2); Can be compounded:

(Scheme 2)

R ⁷ in Scheme 2 is H or an amino-protecting group, L ² is a leaving group, and R ⁴ is as defined for Formula (1).

Compounds of formula 9 may be prepared according to methods known in the art. For example, the compound of formula 9 may be prepared by first preparing ( R ) -5-benzyl- N -methyl-5-azaspiro [2.4] heptan-7-amine in the presence of 6-halo-7-deazapurin and potassium carbonate. by refluxing with heating or reacting the (R) - N - (5- benzyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidine 4-amine can be obtained and prepared by reacting with hydrogen under a palladium / carbon catalyst. In addition, when R ⁷ is an amino-protecting group, it may be introduced according to conventional methods. ( R ) -5-benzyl- N -methyl-5-azaspiro [2.4] heptan-7-amine and 6-halo-7-deazapurin can be synthesized or commercially available by those skilled in the art. The method may optionally further comprise a deprotection step when R ⁷ is an amino-protecting group.

The compound of formula 2 may be prepared by reacting a compound of formula 9 or a salt thereof with a compound of R ⁴ -L ^{2 in} a suitable solvent such as N , N -dimethylformamide. For example, a compound of formula 9 N, N - by reacting at room temperature under the presence of diisopropyl ethyl amine, (R) - - 1-bromo-butane in dimethylformamide, N, N N - ( 5-butyl-5-azaspiro [2.4] heptan-7-yl) -N -methyl-7 H -pyrrolo [2,3- d ] pyrimidin-4-amine can be prepared.

In this way, the compounds of the present invention can be prepared from starting materials that are readily available using common methods and procedures or using other information readily available to those skilled in the art. More specific synthesis procedures of the present invention may be referred to the examples.

Compounds of the present invention, including salts of compounds, and solvates including hydrates, can be prepared using generally known organic synthesis techniques and can be synthesized according to one of a number of possible synthetic routes.

In the present invention, the reactions for synthesizing the compound of Formula 1 may be carried out in a suitable solvent which can be easily selected by those skilled in the art of organic synthesis. Suitable solvents are generally nonreactive with the starting materials or reactants, intermediates or reaction products at the temperature at which the reaction is carried out, ie at temperatures ranging from the freezing point of the solvent to the boiling point of the solvent. The given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a solvent suitable for the specific reaction step can be selected.

In the present invention, the synthesis of the compound of formula 1 may include protection and deprotection of various chemical functional groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art.

The reaction can be followed up according to any suitable method known in the art. For example, the formation of the reaction product may include spectroscopic methods such as nuclear magnetic resonance spectroscopy (eg, ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (eg, UV-visible), and mass spectrometry; Chromatography, such as, high performance liquid chromatography (HPLC) and thin layer chromatography (TLC), can be followed. The compounds of the present invention can be synthesized according to a number of synthetic routes well known in the literature.

A composition according to one aspect is intended to prevent hair loss or to promote hair growth in a mammal comprising a compound of formula (1), or a pharmaceutically, cosmetically or pharmaceutically acceptable salt or solvate or stereoisomer thereof. Can be used.

According to the method according to another aspect, it is possible to effectively prevent hair loss of the individual or to promote hair growth.

1 is a diagram showing the effect of the compound of formula 1 on hair growth in the hair loss model mouse.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Reagents, starting materials and solvents were purchased from commercial suppliers (such as Aldrich, Fluka, Sigma, Acros, Gold, TCI, etc.) and used without further purification unless otherwise noted in this example. Purification used in the synthesis process was performed by flash column chromatography using Merck Silica gel 60 (0.040 ~ 0.063 mm).

1. Intermediate Preparation Example

The compounds prepared in the examples below were synthesized using some of the following intermediates.

(1.1) Intermediate 1: ( R )- N -(5-benzyl-5- Azaspiro [2.4] heptane -7 days)- N - methyl -7 H - Pyrrolo [2,3- d ] Pyrimidine -4-amine

2.000 g of ( R ) -5-benzyl- N -methyl-5-azaspiro [2.4] heptan-7-amine (Sundia, China) was added to a 100 mL round bottom flask, and 40.0 mL of distilled water was added thereto. Then 1.490 g of 6-chloro-7-deazapurine (6-chloro-7-deazapurine) (Acros) was added. 2.560 g of potassium carbonate was added to the reaction mixture. This mixture was refluxed for 36 hours. After 36 hours, the mixture was cooled to room temperature. The reaction mixture was extracted three times with 40.0 mL of dichloromethane. The collected organic layer was concentrated under reduced pressure. The obtained residue was purified using flash column chromatography (MeOH: DCM = 2: 98).

As a result of 2.370 g (R) - N - (5- benzyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin -4 -Amine was obtained with a yield of 77.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.20 (s, 1H), 8.21 (s, 1H), 7.45-7.19 (m, 5H), 7.03 (s, 1H), 6.57 (s, 1H), 5.57 ( s, 1H), 3.64 (dd, J = 31.2, 12.8 Hz, 2H), 3.52 (s, 3H), 2.95 (s, 2H), 2.76 (d, J = 8.8 Hz, 1H), 2.51 (d, J = 8.8 Hz, 1H), 0.95 (d, J = 9.3 Hz, 1H), 0.63 (s, 2H), 0.47 (d, J = 9.7 Hz, 1H).

(1.2) Intermediate 2: ( R )- N -methyl- N -(5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

2.350 g of a 50 mL round bottom flask was added (R) - N - (5- benzyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] Pyrimidin-4-amine was added and dissolved in 25.0 mL of methanol. Then 2.350 g of 10w / w% palladium / carbon (Acros) was added and a hydrogen balloon was placed on the reaction flask. The reaction mixture was stirred vigorously for 39 hours. The reaction mixture was filtered through a layer of Celite ^™ 545 (Crude), a filter agent. The filtered solution was concentrated under reduced pressure.

As a result of 1.510 g (R) - N - methyl - N - (5- azaspiro [2.4] heptan-7-yl) -7 H - pyrrolo [2,3- d] pyrimidin-4-amine 88.0 Obtained in% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.77 (s, 1H), 8.25 (s, 1H), 7.07 (d, J = 3.5 Hz, 1H), 6.58 (d, J = 3.5 Hz, 1H), 5.38 (dd, J = 23.1, 16.5 Hz, 1H), 3.72-3.56 (m, 1H), 3.49 (d, J = 11.7 Hz, 4H), 3.30-3.11 (m, 2H), 2.92 (d, J = 11.2 Hz, 1H), 0.93 (d, J = 10.9 Hz, 1H), 0.82-0.68 (m, 2H), 0.68-0.46 (m, 1H).

Example 1. R )- N -(5-butyl-5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

70.0 mg ( R ) -N -methyl- N- (5-azaspiro [2.4] heptan-7-yl) -7 H -pyrrolo [2,3- d ] pyrimidine-4 in a 5 mL round bottom flask -Amine was added and dissolved in 1.0 mL of N , N -dimethylformamide. 59.3 mg of 1-bromobutane (Sigma-Aldrich) was added to this solution. Thereafter, 0.100 mL of N , N -diisopropylethylamine (large gold) was added. The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was purified by column (MeOH: DCM = 2: 98). The resulting liquid was concentrated under reduced pressure and concentrated in vacuo. The resulting 35.0 mg (R) - N - (5- butyl-5-azaspiro [2.4] heptan-7-yl) - N - methyl -7 H - pyrrolo [2,3- d] pyrimidin -4 -Amine was obtained in a yield of 40.7%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.23 (s, 1H), 7.02 (s, 1H), 6.61 (s, 1H), 5.56 (s, 1H), 3.49 (s, 3H), 2.96 (s, 2H), 2.78 (s, 1H), 2.52 (s, 3H), 1.53-1.51 (m, 2H), 1.44-1.35 (m, 2H), 0.97 (t, J = 7.2 Hz , 4H), 0.74 (s, 2H), 0.51 (d, J = 9.2 Hz, 1H). LRMS (ESI) calcd for (C ₁₇ H ₂₅ N ₅ + H ⁺ ) 300.2, found 300.2.

Additional compounds of the invention described below were synthesized via methods analogous to the synthesis described in Example 1 exemplified above.

Example 2. R )- N -methyl- N -(5-pentyl-5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.29 (s, 1H), 8.20 (s, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 5.57 (s, 1H), 3.49 (s, 3H), 3.14-2.99 (m, 2H), 2.81 (s, 1H), 2.57-2.48 (m, 3H), 1.71-1.66 (m, 4H), 1.37-1.33 (m, 2H), 0.97-0.91 (m, 4H), 0.79-0.66 (m, 2H), 0.55-0.50 (m, 1H). LRMS (ESI) calcd for (C ₁₈ H ₂₇ N ₅ + H ⁺ ) 314.2, found 314.2.

Example  3. ( R )-2- methyl -1- (7- (methyl (7 H - Pyrrolo [2,3- d ] Pyrimidine -4-yl) amino) -5-a Jaspiro [2.4] hep Tan-5-yl) propan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 10.00 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.09-7.02 (m, 1H), 6.60-6.57 ( m, 1H), 5.54-5.41 (m, 1H), 4.20-3.79 (m, 2H), 3.48-3.38 (m, 4H), 2.74-2.59 (m, 1H), 1.20-1.15 (m, 6H), 1.10-1.01 (m, 1 H), 0.90-0.65 (m, 3 H). LRMS (ESI) calcd for (C ₁₇ H ₂₃ N ₅ O + H ⁺ ) 314.2, found 314.2.

Example 4. R ) -2-azido-1- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (s, 1H), 8.25 (d, J = 3.2 Hz, 1H), 7.09-7.02 (m, 1H), 6.70-6.59 (m, 1H), 5.52- 5.44 (m, 1H), 4.16-4.07 (m, 1H), 3.99-3.85 (m, 3H), 3.84-3.57 (m, 2H), 3.55-3.32 (m, 3H), 1.15-1.00 (m, 1H ), 0.92-0.74 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₁₈ N ₈ O + H ⁺ ) 327.2, found 327.1.

Example 5. R ) -3- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.24 (s, 1H), 8.24 (d, J = 4.6 Hz, 1H), 7.16-6.95 (m, 1H), 6.57 (dd, J = 7.2, 3.5 Hz, 1H), 5.63-5.34 (m, 1H ), 4.27-4.02 (m, 1H), 4.01-3.83 (m, 1H), 3.76 (dd, J = 11.4, 2.3 Hz, 1H), 3.51 (d, J = 12.4 Hz, 2H), 3.48-3.35 (m, 4H), 1.17-0.96 (m, 1H), 0.84 (ddd, J = 19.4, 10.7, 4.3 Hz, 3H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2.

Example 6. R ) -3-methyl-1- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) butan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.60 (d, J = 8.8 Hz, 1H) , 5.47-5.36 (m, 1H), 4.16-3.74 (m, 3H), 3.49-3.38 (m, 4H), 2.29-2.18 (m, 3H), 1.09-0.98 (m, 7H), 0.90-0.73 ( m, 3H). LRMS (ESI) calcd for (C ₁₈ H ₂₅ N ₅ O + H ⁺ ) 328.2, found 328.2.

Example 7. R )- N -(2- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl) acetamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.53 (d, J = 14.4 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.11 (s, 1H), 6.72 (d, J = 18.4 Hz , 1H), 6.58 (s, 1H), 5.46 (dd, J = 31.6, 6.4 Hz, 1H), 4.13-4.06 (m, 2H), 4.01-3.94 (m, 1H), 3.92-3.83 (m, 1H ), 3.73 (d, J = 11.6 Hz, 1H), 3.52 (d, J = 12.4 Hz, 1H), 3.43-3.40 (m, 3H), 2.07 (d, J = 4.0 Hz, 3H), 1.11-1.01 (m, 1 H), 0.90-0.80 (m, 3 H). LRMS (ESI) calcd for (C ₁₇ H ₂₂ N ₆ O ₂ + H ⁺ ) 343.2, found 343.1.

Example 8. R )- N -Methyl-3- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.96 (d, J = 30.6 Hz, 1H), 8.24 (dd, J = 6.6, 1.8 Hz, 1H), 8.13 (s, 1H), 7.11 (s, 1H) , 6.54 (s, 1H), 5.51-5.34 (m, 1H), 4.13 (ddd, J = 21.2, 12.6, 7.5 Hz, 1H), 4.00-3.80 (m, 2H), 3.49 (t, J = 11.6 Hz , 1H), 3.40 (d, J = 14.5 Hz, 3H), 3.35 (t, J = 19.8 Hz, 2H), 2.83 (dd, J = 4.5, 2.1 Hz, 3H), 1.11-0.94 (m, 1H) , 0.90-0.68 (m, 3 H). LRMS (ESI) calcd for (C ₁₇ H ₂₂ N ₆ O ₂ + H ⁺ ) 343.2, found 343.1.

Example 9. R ) -Cyclopropyl (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.32 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 11.6 Hz , 1H), 5.56-5.39 (m, 1H), 4.36-3.86 (m, 3H), 3.65-3.36 (m, 4H), 1.69-1.55 (m, 1H), 1.11-0.94 (m, 3H), 0.81 -0.71 (m, 5 H). LRMS (ESI) calcd for (C ₁₇ H ₂₁ N ₅ O + H ⁺ ) 312.2, found 312.1.

Example 10. R ) -1- (4- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) piperidin-1-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.80 (s, 1H), 8.28 (dd, J = 9.6, 3.2 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 5.49-5.40 ( m, 1H), 4.64 (t, J = 12.4 Hz, 1H), 4.23-4.02 (m, 1H), 4.00-3.78 (m, 3H), 3.52-3.49 (m , 1H), 3.46 (s, 3H), 3.39 (s, 1H), 3.15-3.10 (m, 1H), 2.66-2.56 (m, 2H), 2.13-2.04 (m, 3H), 1.88-1.70 (m , 2H), 1.12-1.00 (m, 1H), 0.94-0.76 (m, 4H). LRMS (ESI) calcd for (C ₂₁ H ₂₈ N ₆ O ₂ + H ⁺ ) 397.2, found 397.2.

Example 11. R ) -Furan-2-yl (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.91 (s, 1H), 8.28 (s, 1H), 7.54 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.08 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 6.53 (s, 1H), 5.49 (d, J = 6.8 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.15-4.10 (m, 1H), 3.84-3.64 (m, 1H), 3.45 (s, 3H), 1.06 (s, 1H), 0.90-0.80 (m, 3H). LRMS (ESI) calcd for (C ₁₈ H ₁₉ N ₅ 0 ₂ + H ⁺ ) 338.2, found 338.1.

Example 12. R )-(7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-3-yl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.27 (d, J = 25.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.05 (s, 1H), 6.61 (d, J = 21.6 Hz, 1H), 5.59-5.35 (m, 1H), 4.29-4.10 (m, 2H), 3.88-3.43 (m, 5H), 1.08-1.05 (m, 1H), 0.91-0.80 (m, 2H), 0.69 (s, 1H). LRMS (ESI) calcd for (C 19 H 20 N 6 O + H +) 349.2, found 349.2.

Example 13. R )-(7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 8.23 (d, J = 26.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.44 (s, 3H), 7.04 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 22.0 Hz, 1H), 5.47 (d, J = 78.0 Hz, 1H), 4.27-4.11 (m, 2H), 3.84-3.62 (m, 2H), 3.45 (d, J = 20.0 Hz, 3H), 1.05 (s, 1H), 0.89-0.66 (m, 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₁ N ₅ O + H ⁺ ) 348.2, found 348.2.

Example 14. R )-(7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-4-yl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.49 (s, 1H), 8.75 (dd, J = 11.6, 5.6 Hz, 2H), 8.28 (d, J = 26.0 Hz, 1H), 7.42-7.41 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 17.6 Hz, 1H), 5.58-5.36 (m, 1H), 4.31-4.08 (m, 2H), 3.77-3.42 (m , 5H), 1.08-1.05 (m, 1H), 0.99-0.80 (m, 2H), 0.72-0.61 (m, 1H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ N ₆ O + H ⁺ ) 349.2, found 349.1.

Example 15. R ) -3- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 8.25 (d, J = 24.4 Hz, 1H), 7.86 (s, 1H), 7.82-7.73 (m, 2H), 7.58-7.54 ( m, 1H), 7.07-7.02 (m, 1H), 6.61-6.57 (m, 1H), 5.60-5.35 (m, 1H), 4.29-4.09 (m, 2H), 3.84-3.63 (m, 1H), 3.44-3.42 (m, 3H), 1.27 (s, 1H), 1.09-1.04 (m, 1H), 0.94-0.79 (m, 3H). LRMS (ESI) calcd for (C ₂₁ H ₂₀ N ₆ O + H ⁺ ) 373.2, found 373.1.

Example 16. R ) -4- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H), 8.28 (d, J = 26.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.67 (d, J = 8.0 Hz, 2H) , 7.10 (d, J = 10.4 Hz, 1H), 6.60 (d, J = 20.4 Hz, 1H), 5.59 (m, 1H), 4.36-4.02 (m, 2H), 3.79-3.18 (m, 5H), 1.08-1.05 (m, 1 H), 0.99-0.73 (m, 2 H), 0.68 (s, 1 H). LRMS (ESI) calcd for (C ₂₁ H ₂₀ N ₆ O + H ⁺ ) 373.2, found 373.2.

Example 17. R )-(7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (2- (trifluoromethyl) phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 8.35 (d, J = 32.4 Hz, 1H), 7.80-7.51 (m, 3H), 7.43 (d, J = 7.2 Hz, 1H) , 7.08 (d, J = 9.6 Hz, 1H), 6.61 (d, J = 16.8 Hz, 1H), 5.63-5.36 (m, 1H), 4.27-3.86 (m, 2H), 3.69-3.11 (m, 5H ), 1.15-1.05 (m, 1H), 0.94-0.81 (m, 2H), 0.75-0.54 (m, 1H). LRMS (ESI) calcd for (C ₂₁ H ₂₀ F ₃ N ₅ O + H ⁺ ) 416.2, found 416.1.

Example 18. R )-(7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (3- (trifluoromethyl) phenyl) methanone

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 8.27 (d, J = 26.0 Hz, 1H), 7.84 (s, 1H), 7.76-7.70 (m, 2H), 7.61-7.56 ( m, 1H), 7.09 (d, J = 10.4 Hz, 1H), 6.61 (d, J = 20.4 Hz, 1H), 5.64-5.37 (m, 1H), 4.36-4.05 (m, 2H), 3.86-3.37 (m, 5H), 1.11 (d, J = 13.6 Hz, 1H), 0.99-0.69 (m, 3H). LRMS (ESI) calcd for (C ₂₁ H ₂₀ F ₃ N ₅ O + H ⁺ ) 416.2, found 416.1.

Example 19. R ) -3- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.07 (s, 1H), 8.27 (d, J = 3.4 Hz, 1H), 7.20-7.08 (m, 1H), 6.57 (dd, J = 5.7, 3.7 Hz, 1H), 5.45 (tt, J = 186.7, 93.9 Hz, 1H), 4.42-4.25 (m, 1H), 4.20 (dd, J = 131.3, 13.0 Hz, 1H), 4.01 (dd, J = 162.4, 14.4 Hz , 1H), 3.98-3.85 (m, 2H), 3.90 (dd, J = 211.1, 11.8 Hz, 1H), 3.44 (t, J = 19.7 Hz, 3H), 1.16-1.00 (m, 1H), 0.97- 0.74 (m, 3 H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ S + H ⁺ ) 327.1, found 327.1.

Example 20. Isobutyl ( R ) -7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.72 (s, 1H), 8.26 (s, 1H), 7.09 (s, 1H), 6.58 (s, 1H), 5.42 (d, J = 5.6 Hz, 1H) , 4.06-4.02 (m, 1H), 3.93 (d, J = 5.6 Hz, 2H), 3.81-3.72 (m, 2H), 3.43-3.34 (m, 4H), 2.01-1.91 (m, 1H), 1.02 -0.88 (m, 7H), 0.78 (d, J = 9.6 Hz, 3H). LRMS (ESI) calcd for (C ₁₈ H ₂₅ N ₅ 0 ₂ + H ⁺ ) 344.2, found 344.2.

Example 21. R )- N -Butyl-7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.20 (s, 1H), 8.25 (s, 1H), 7.09 (d, J = 3.3 Hz, 1H), 6.54 (s, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.36 (s, 1H), 3.97 (dd, J = 10.9, 7.4 Hz, 1H), 3.74 (d, J = 9.8 Hz, 1H), 3.65 (dd, J = 11.0, 1.6 Hz, 1H), 3.41 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 3.26 (dd, J = 13.2, 6.4 Hz, 2H), 1.66-1.42 (m, 2H), 1.35 (dq, J = 14.2, 7.3 Hz, 2H), 0.99 (d, J = 9.2 Hz, 1H), 0.92 (dd, J = 7.8, 6.7 Hz, 3H), 0.75 (s, 3H). LRMS (ESI) calcd for (C ₁₈ H ₂₆ N ₆ O + H ⁺ ) 343.2, found 343.2.

Example 22. R )- N -Cyclohexyl-7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.87 (s, 1H), 8.26 (s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.11 (d, J = 7.8 Hz, 1H), 3.97 (dd, J = 10.9, 7.4 Hz, 1H), 3.74 (d, J = 9.9 Hz, 1H), 3.71 -3.66 (m, 1H), 3.63 (dd, J = 11.0, 1.7 Hz, 1H), 3.42 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 1.97 (d, J = 11.5 Hz, 2H), 1.69 (dd, J = 8.7, 4.1 Hz, 2H), 1.61 (d, J = 12.7 Hz, 1H), 1.37 (dd, J = 23.1, 11.4 Hz, 2H), 1.21-1.03 (m, 3H ), 0.99 (dd, J = 15.2, 8.0 Hz, 1H), 0.77 (s, 3H). LRMS (ESI) calcd for (C 20 H 28 N 6 O + H +) 369.2, found 369.2.

Example 23. R ) -7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino)- N -Phenyl-5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.98 (s, 1H), 8.27 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.27 (dd, J = 9.1, 6.7 Hz, 2H) , 7.09 (d, J = 3.3 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 6.44 (s, 1H), 5.42 (d, J = 6.5 Hz, 1H), 4.09 (dd, J = 10.9, 7.5 Hz, 1H), 3.86 (d, J = 10.0 Hz, 1H), 3.82-3.73 (m, 1H), 3.45 (s, 1H), 3.43 ( s, 3H), 1.08-0.99 (m, 1H), 0.78 (s, 3H). LRMS (ESI) calcd for (C 20 H 22 N 6 O + H +) 363.2, found 363.2.

Example 24. R )- N -(4-fluorophenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.27 (s, 1H), 7.40-7.37 (m, 2H), 7.10-7.09 (m, 1H), 7.03-6.99 (m, 2H ), 6.61 (s, 1H) , 6.19 (s, 1H), 5.46 (d, J = 5.6 Hz, 1H), 4.15 (dd, J = 10.8, 7.2 Hz, 1H), 3.91 (d, J = 10.0 Hz , 1H), 3.81 (dd, J = 11.2, 2.0 Hz, 1H), 3.48-3.46 (m, 4H), 1.11-1.02 (m, 1H), 0.90-0.84 (m, 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₁ FN ₆ O + H ⁺ ) 381.2, found 381.2.

Example 25. R )- N -(2,4-dichlorophenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.27 (s, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.27 -7.24 (m, 1H), 7.10 (t, J = 2.8 Hz, 1H), 6.83 (s, 1H), 6.61 (s, 1H), 5.53 (d, J = 6.4 Hz, 1H), 4.20 (dd, J = 11.2, 7.6 Hz, 1H), 3.92 (d, J = 9.6 Hz, 1H), 3.85 (d, J = 10.0 Hz, 1H), 3.50 (m, 4H), 1.11 (d, J = 11.2 Hz, 1H), 0.90-0.85 (m, 3H). LRMS (ESI) calcd for (C 20 H 20 Cl 2 N 6 O + H +) 431.1, found 431.1.

Example 26. R )- N -(3,4-dichlorophenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 8.27 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.10-7.09 (m, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.26 (s, 1H), 5.45 (d, J = 5.6 Hz, 1H) , 4.14 (dd, J = 10.8, 7,2 Hz, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.48 (s, 3H), 3.46 ( s, 1H), 1.09-1.06 (m, 1H), 0.90-0.85 (m, 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ Cl ₂ N ₆ O + H ⁺ ) 431.1, found 431.1.

Example 27. R )- N -(2,5-dichlorophenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.92 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 7.27 (s, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.97 ( dd, J = 8.4, 2.4 Hz, 1H), 6.89 (s, 1H), 6.62 (d, J = 1.6 Hz, 1H), 5.55 (d, J = 6.4 Hz, 1H) , 4.19 (dd, J = 11.2, 7.6 Hz, 1H), 3.92 (d, J = 10.0 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.51 (s, 1H), 3.49 (s, 3H), 1.10 (d, J = 11.2 Hz, 1H), 0.94-0.85 (m, 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ Cl ₂ N ₆ O + H ⁺ ) 431.1, found 431.1.

Example 28. R )- N -(2,3-dichlorophenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.03 (s, 1H), 8.39-8.21 (m, 2H), 7.19 (t, J = 8.2 Hz, 1H), 7.13 (dd, J = 3.9, 3.3 Hz, 2H), 6.97 (s, 1H), 6.58 (d, J = 3.4 Hz, 1H), 5.55 (d, J = 6.3 Hz, 1H), 4.17 (dd, J = 11.2, 7.5 Hz, 1H), 3.88 ( dd, J = 22.4, 10.5 Hz, 2H), 3.50 (s, 1H), 3.47 (s, 3H), 1.14-1.01 (m, 1H), 0.84 (s, 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ Cl ₂ N ₆ O + H ⁺ ) 431.1, found 431.0.

Example 29. R )- N -(3-chloro-4-methylphenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

^{1 H NMR (400 MHz, CDCl} 3) δ 11.92 (s, 1H), 8.25 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H) , 7.08 (s, 1H), 7.06 (d, J = 5.2 Hz, 1H), 6.56 (s, 1H), 6.53 (d, J = 3.4 Hz, 1H), 5.39 (d, J = 6.2 Hz, 1H) , 4.06 (dd, J = 11.1, 7.4 Hz, 1H), 3.82 (d, J = 10.1 Hz, 1H), 3.77 (dd, J = 11.1, 1.5 Hz, 1H), 3.46-3.35 (m, 4H), 2.28 (s, 3 H), 1.05-0.96 (m, 1 H), 0.82-0.71 (m, 3 H). LRMS (ESI) calcd for (C ₂₁ H ₂₃ ClN ₆ O + H ⁺ ) 411.2, found 411.1.

Example 30. R )- N -([1,1'-biphenyl] -2-yl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.27 (s, 1H), 8.24 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.51-7.30 (m, 6H), 7.21 (d, J = 7.2 Hz, 1H), 7.10 (dd, J = 9.2, 5.5 Hz, 2H), 6.55 (d, J = 2.9 Hz, 1H), 6.38 (s, 1H), 5.34 (d, J = 6.4 Hz, 1H), 3.82 (dd, J = 10.9, 7.5 Hz, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.48 (d, J = 10.1 Hz, 1H), 3.38 (s, 3H), 3.20 ( d, J = 9.9 Hz, 1H), 1.04-0.95 (m, 1H), 0.78-0.59 (m, 3H). LRMS (ESI) calcd for (C ₂₆ H ₂₆ N ₆ O + H ⁺ ) 439.2, found 439.2.

Example 31. R )- N -(3,5-bis (trifluoromethyl) phenyl) -7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbothioamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.64 (s, 1H), 8.25 (s, 1H), 7.96 (s, 2H), 7.65 (s, 1H), 7.41 (s, 1H), 7.10 (d, J = 3.4 Hz, 1H), 6.57 (d, J = 3.4 Hz, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.31 (s, 1H), 4.17 (s, 1H), 4.08 (s, 1H), 3.75 (s, 1H), 3.46 (s, 3H), 1.05 (d, J = 5.7 Hz, 1H), 0.87 (d, J = 8.1 Hz, 3H). LRMS (ESI) calcd for (C ₂₂ H ₂₀ F ₆ N ₆ S + H ⁺ ) 515.1, found 515.1.

Example 32. R )- N -methyl- N -(5-((trifluoromethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.34 (s, 1H), 8.26 (s, 1H), 7.12 (s, 1H), 6.61 (s, 1H), 5.56 (dd, J = 7.6, 3.2 Hz, 1H), 4.19 (dd, J = 11.6, 7.6 Hz, 1H), 3.93-3.85 (m, 2H), 3.53-3.49 (m, 4H), 1.12-1.05 (m, 1H), 0.89-0.83 (m, 3H). LRMS (ESI) calcd for (C ₁₄ H ₁₆ F ₃ N ₅ O ₂ S + H ⁺ ) 376.1, found 376.1.

Example 33. R )- N -(5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.53 (s, 1H), 8.25 (s, 1H), 7.10-7.09 (m, 1H), 6.61 (s, 1H), 5.58 (dd, J = 5.3, 2.8 Hz, 1H), 3.96 (dd, J = 11.2, 7.6 Hz, 1H), 3.72-3.68 (m, 2H), 3.50 (s, 3H), 3.37 (d, J = 9.6 Hz, 1H), 3.12 (q , J = 7.0 Hz, 2H), 1.47 (t, J = 7.4 Hz, 3H), 1.10-1.03 (m, 1H), 0.86-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₂₁ N ₅ 0 ₂ S + H ⁺ ) 336.2, found 336.1.

Example 34. R )- N -(5- (isopropylsulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 8.25 (s, 1H), 7.07 (s, 1H), 6.60 (s, 1H), 5.53 (d, J = 4.4 Hz, 1H) , 4.01 (dd, J = 11.2, 7.6 Hz, 1H), 3.77-3.71 (m, 2H), 3.49 (s, 3H), 3.40 (d, J = 9.6 Hz, 1H), 3.33-3.27 (m, 1H ), 1.44 (d, J = 6.4 Hz, 6H), 1.11-1.01 (m, 1H), 0.90-0.75 (m, 3H). LRMS (ESI) calcd for (C 16 H 23 N 5 O 2 S + H +) 350.2, found 350.2.

Example 35. R )- N -methyl- N -(5- (propylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 8.25 (s, 1H), 7.09 (s, 1H), 6.60 (s, 1H), 5.82-5.55 (m, 1H), 3.92 ( dd, J = 10.8, 7.6 Hz, 1H), 3.70-3.67 (m, 2H), 3.50 (s, 3H), 3.35 (d, J = 10.0 Hz, 1H), 3.05-3.01 (m, 2H), 2.06 -1.90 (m, 2H), 1.13 (t, J = 7.6 Hz, 3H), 1.07-1.02 (m, 1H), 0.86-0.71 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₂₃ N ₅ 0 ₂ S + H ⁺ ) 350.2, found 350.1.

Example 36. R )- N -methyl- N -(5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.74-7.57 (m, 3H), 7.05 (s, 1H), 6.56 (s, 1H), 5.45 (t, J = 5.0 Hz, 1H), 3.68-3.59 (m, 2H), 3.57 (d, J = 5.6 Hz, 1H), 3.36 (s, 3H), 3.10 (d, J = 9.6 Hz, 1H), 0.93-0.87 (m, 1H), 0.84-0.72 (m, 1H), 0.67-0.59 (m, 2H). LRMS (ESI) calcd for (C ₁₉ H ₂₁ N ₅ 0 ₂ S + H ⁺ ) 384.2, found 384.1.

Example 37. R )- N -(5-((2-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.52 (s, 1H), 8.19 (s, 1H), 7.95-7.91 (m, 1H), 7.66-7.61 (m, 1H), 7.34-7.25 (m, 2H ), 7.25 (s, 1H) , 6.57 (s, 1H), 5.49-5.46 (m, 1H), 3.85 (dd, J = 11.2, 7.6 Hz, 1H), 3.72-3.69 (m, 2H), 3.43 ( s, 3H), 3.30 (d, J = 9.6 Hz, 1H), 0.98-0.88 (m, 1H), 0.82-0.77 (m, 1H), 0.74-0.65 (m, 2H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ FN ₅ O ₂ S + H ⁺ ) 402.1, found 402.1.

Example 38. R )- N -(5-((3-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.18 (s, 1H), 7.67-7.54 (m, 3H), 7.40-7.33 (m, 1H), 7.06-7.02 (m, 1H ), 6.57-6.56 (m, 1H) , 5.46-5.44 (m, 1H), 3.65-3.62 (m, 2H), 3.59 (d, J = 9.6 Hz, 1H), 3.38 (s, 3H), 3.12 ( d, J = 9.6 Hz, 1H), 0.96-0.91 (m, 1H), 0.80-0.74 (m, 1H), 0.69-0.68 (m, 2H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ FN ₅ O ₂ S + H ⁺ ) 402.1, found 402.1.

Example 39. R )- N -(5-((4-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (s, 1H), 8.18 (s, 1H), 7.94-7.85 (m, 2H), 7.27-7.24 (m, 2H), 7.06-6.99 (m, 1H ), 6.57-6.55 (m, 1H), 5.46 (dd, J = 6.4, 1.6 Hz, 1H), 3.71-3.53 (m, 3H), 3.38 (s, 3H), 3.09 (d, J = 9.6 Hz, 1H), 0.95-0.88 (m, 1H), 0.82-0.74 (m, 1H), 0.69-0.60 (m, 2H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ FN ₅ O ₂ S + H ⁺ ) 402.1, found 402.1.

Example 40. R ) -2-((7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.19 (s, 1H), 8.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (dd, J = 7.2, 1.2 Hz, 1H), 7.81-7.73 (m, 2H), 7.08-7.02 (m, 1H), 6.58-6.56 (m, 1H), 5.52 (dd, J = 7.6, 6.8 Hz, 1H), 3.85-3.74 (m, 2H), 3.72 (dd, J = 10.8, 3.0 Hz, 1H), 3.43 (s, 3H), 3.41 (d, J = 10.0 Hz, 1H), 1.06-0.94 (m, 1H), 0.88-0.69 (m , 3H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ N ₆ 0 ₂ S + H ⁺ ) 409.1, found 409.1.

Example 41. R ) -3-((7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.09-8.07 (m, 1H), 7.95-7.93 (m, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.08-7.02 (m, 1H), 6.56-6.55 (m, 1H), 5.44-5.32 (m, 1H), 3.69-3.61 (m, 3H), 3.39 ( s, 3H), 3.13 (d, J = 9.6 Hz, 1H), 0.98-0.88 (m, 1H), 0.84-0.77 (m, 1H), 0.73-0.63 (m, 2H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ N ₆ 0 ₂ S + H ⁺ ) 409.1, found 409.1.

Example 42. R ) -4-((7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.99 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 6.55 (s, 1H), 5.39-5.37 (m, 1H), 3.68-3.65 (m, 2H), 3.62 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H), 3.13 (d, J = 9.6 Hz, 1H), 0.99-0.91 (m, 1H), 0.85-0.74 (m, 1H), 0.72-0.62 (m, 2H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ N ₆ 0 ₂ S + H ⁺ ) 409.1, found 409.1.

Example 43. R )- N -methyl- N -(5-((2-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

^{1 H NMR (400 MHz, CDCl} 3) δ 9.67 (s, 1H), 8.22 (s, 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.78-7.66 (m, 3H), 7.07 ( t, J = 2.4 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 5.52 (dd, J = 7.6, 2.4 Hz, 1H), 3.96 (dd, J = 10.8, 7.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.43 (s, 3H), 3.41 (s, 1H), 1.03-0.99 (m, 1H), 0.92-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ N ₆ O ₄ S + H ⁺ ) 429.1, found 429.1.

Example 44. R )- N -methyl- N -(5-((3-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 8.22 (s, 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.78-7.66 (m, 3H), 7.07 ( t, J = 2.4 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 5.52 (dd, J = 7.6, 2.4 Hz, 1H), 3.96 (dd, J = 10.8, 7.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.43 (s, 3H), 3.41 (s, 1H), 1.03-0.99 (m, 1H), 0.92-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ N ₆ O ₄ S + H ⁺ ) 429.1, found 429.1.

Example 45. R )- N -methyl- N -(5-((4-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 8.19 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.07 (t, J = 2.4 Hz, 1H), 6.53 (t, J = 1.6 Hz, 1H), 5.39-5.36 (m, 1H), 3.72-3.67 (m, 2H), 3.64 (d, J = 9.6 Hz, 1H), 3.38 (s, 3H), 3.14 (d, J = 9.6 Hz, 1H), 0.96-0.89 (m, 1H), 0.88-0.79 (m, 1H), 0.75-0.63 (m, 2H). LRMS (ESI) calcd for (C ₁₉ H ₂₀ N ₆ O ₄ S + H ⁺ ) 429.1, found 429.1.

Example 46. R )- N -methyl- N -(5- (m-tolylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.19 (s, 1H), 7.66 (s, 2H), 7.47-7.46 (m, 2H), 7.06 (s, 1H), 6.55 ( s, 1H), 5.45-5.43 (m, 1H), 3.61-3.52 (m, 3H), 3.37 (s, 3H), 3.10-3.07 (d, J = 9.6 Hz, 1H), 2.46 (s, 3H) , 0.93-0.88 (m, 1H), 0.79-0.73 (m, 1H), 0.67-0.59 (m, 2H). LRMS (ESI) calcd for (C ₂₀ H ₂₃ N ₅ 0 ₂ S + H ⁺ ) 398.2, found 398.1.

Example 47. R )- N -(5-((4-methoxyphenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 3H), 6.61 (s, 1H), 5.46 (s, 1H), 3.92 (s, 3H), 3.61-3.55 (m, 2H), 3.53 (m, 1H), 3.38 (s, 3H), 3.07 (d, J = 9.6 Hz, 1H), 0.94-0.90 (m, 1H), 0.82-0.72 (m, 1H), 0.66-0.59 (m, 2H). LRMS (ESI) calcd for (C ₂₀ H ₂₃ N ₅ 0 ₃ S + H ⁺ ) 414.2, found 414.1.

Example 48. R )- N -methyl- N -(5-((4- (trifluoromethyl) phenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.54 (s, 1H), 5.43-5.32 (m, 1H), 3.69-3.58 (m, 3H), 3.37 (s, 3H), 3.13 (d, J = 9.6 Hz, 1H), 0.97-0.88 (m, 1 H), 0.81-0.75 (m, 1 H), 0.71-0.62 (m, 2H). LRMS (ESI) calcd for (C ₂₀ H ₂₀ F ₃ N ₅ O ₂ S + H ⁺ ) 452.1, found 452.1.

Example 49. R )- N -methyl- N -(5- (naphthalen-2-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 8.03-7.96 (m, 3H), 7.87 (dd, J = 8.8, 5.6 Hz, 1H), 7.72-7.59 (m, 2H), 7.03 (s, 1H), 6.57 (s, 1H), 5.54-5.41 (m, 1H), 3.75-3.63 (m, 2H), 3.62 (d, J = 9.6 Hz, 1H), 3.36 (s, 3H), 3.17 (d, J = 9.6 Hz, 1H), 0.90-0.84 (m, 1H), 0.78-0.72 (m, 1H), 0.68-0.57 (m , 2H). LRMS (ESI) calcd for (C ₂₃ H ₂₃ N ₅ O ₂ S + H ⁺ ) 434.2, found 434.1.

Example 50. R )- N -methyl- N -(5- (piperidin-1-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.81 (s, 1H), 8.24 (s, 1H), 7.07-7.00 (m, 1H), 6.60-6.59 (m, 1H), 5.52 (d, J = 5.2 Hz, 1H), 3.87 (dd, J = 10.8, 7.6 Hz, 1H), 3.57-3.54 (m, 2H), 3.49 (s, 3H), 3.31-3.28 (m, 4H), 1.81-1.58 (m, 7H), 1.04-1.01 (m, 1H), 0.82-0.74 (m, 2H), 0.71-0.68 (m, 1H). LRMS (ESI) calcd for (C ₁₈ H ₂₆ N ₆ 0 ₂ S + H ⁺ ) 391.2, found 391.1.

Example 51. R )- N -methyl- N -(5- (morpholinosulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 8.25 (s, 1H), 7.08-7.07 (m, 1H), 6.65-6.59 (m, 1H), 5.58 (dd, J = 7.6 , 2.8 Hz, 1H), 3.93 (dd, J = 10.8, 7.6 Hz, 1H), 3.78 (t, J = 4.8 Hz, 4H), 3.65-3.59 (m, 2H), 3.48 (s, 3H), 3.34 -3.30 (m, 5H), 1.10-1.02 (m, 1H), 0.83-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₇ H ₂₄ N ₆ O ₃ S + H ⁺ ) 393.2, found 393.1.

Example 52. 1- (7- (Methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 8.32-8.16 (m, 1H), 7.07 (s, 1H), 6.57 (s, 1H), 5.63-5.31 (m, 1H), 4.19-3.97 (m, 2H), 3.97-3.66 (m, 2H), 3.55-3.43 (m, 1H), 3.43-3.26 (m, 3H), 2.32 (dq, J = 14.4, 7.3 Hz, 1H), 1.23-1.12 (m, 2H), 1.10-0.93 (m, 1H), 0.91-0.63 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₂₁ N ₅ O + H ⁺ ) 300.2, found 300.3.

Example 53. 2-methoxy-1- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.09 (s, 1H), 8.23 (s, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.57 (d, J = 3.1 Hz, 1H), 5.38 (d, J = 5.7 Hz, 1H), 4.07 (d, J = 7.5 Hz, 1H), 3.96 (dd, J = 11.0, 7.4 Hz, 1H), 3.73 (d, J = 9.9 Hz, 1H), 3.62 (dd, J = 11.0, 2.2 Hz, 1H), 3.42 (s, 3H), 1.44-1.30 (m, 2H), 1.21-1.04 (m, 3H), 1.03-0.95 (m, 1H), 0.84-0.68 (m, 3 H). LRMS (ESI) calcd for (C ₁₆ H ₂₁ N ₅ O ₂ + H ⁺ ) 316.2, found 316.1.

Example 54. 2-azido-1- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.98 (s, 1H), 8.37-8.03 (m, 1H), 7.17-6.97 (m, 1H), 6.69-6.45 (m, 1H), 5.63-5.32 (m , 1H), 4.15-4.00 (m, 1H), 3.99-3.75 (m, 3H), 3.69-3.48 (m, 2H), 3.48-3.27 (m, 3H), 1.04-0.93 (m, 1H), 0.91 -0.64 (m, 3 H). LRMS (ESI) calcd for (C ₁₅ H ₁₈ N ₈ O + H ⁺ ) 327.2, found 327.2.

Example 55. 3- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile

^{1 H NMR (400 MHz, CDCl} 3) δ 9.55 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 7.15-7.03 (m, 1H), 6.61 (s, 1H), 5.58-5.35 ( m, 1H), 4.26-4.03 (m, 1H), 4.02-3.91 (m, 1H), 3.89-3.72 (m, 1H), 3.72-3.51 (m, 2H), 3.48 (d, J = 7.7 Hz, 2H), 3.45-3.32 (m, 2H), 1.19-0.99 (m, 1H), 0.95-0.68 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2.

Example 56. N -(2- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl) acetamide

^{1 H NMR (400 MHz, CDCl} 3) δ 10.18 (d, J = 14.5 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 7.08 (dd, J = 18.0, 14.6 Hz, 1H), 6.68 (d, J = 17.3 Hz, 1H), 6.58 (d, J = 3.1 Hz, 1H), 5.55-5.35 (m, 1H), 4.17-4.03 (m, 2H), 4.03-3.93 (m, 1H), 3.87 (dd, J = 27.0, 11.3 Hz, 1H), 3.78-3.68 (m, 1H), 3.57-3.48 (m, 1H), 3.46-3.33 (m, 3H), 2.08 (d, J = 4.2 Hz, 3H), 1.14-0.97 (m, 1 H), 0.94-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₇ H ₂₂ N ₆ O ₂ + H ⁺ ) 343.2, found 343.2.

Example 57. N -Methyl-3- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.89 (s, 1H), 8.24 (d, J = 4.2 Hz, 1H), 8.08 (s, 1H), 7.17-7.05 (m, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.43 (t, J = 7.8 Hz, 1H), 5.30 (s, 1H), 4.13 (ddd, J = 21.2, 12.7, 7.5 Hz, 1H), 3.91 (dd, J = 46.8 , 11.7 Hz, 1H), 3.99-3.81 (m, 1H), 3.49 (t, J = 11.0 Hz, 1H), 3.42 (s, 1H), 3.37 (t, J = 10.0 Hz, 3H), 2.84 (dd , J = 4.7, 2.5 Hz, 3H), 1.10-0.95 (m, 1H), 0.89-0.72 (m, 3H). LRMS (ESI) calcd for (C ₁₇ H ₂₂ N ₆ O ₂ + H ⁺ ) 343.2, found 343.1.

Example 58. 3-Amino-1- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one

¹ H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.08 (d, J = 3.1 Hz, 1H), 7.92 (s, 2H), 7.17 (d, J = 2.4 Hz, 1H), 6.61 ( s, 1H), 5.39-5.06 (m, 1H), 4.20-3.57 (m, 3H), 3.32-3.24 (m, 4H), 3.11-2.90 (m, 2H), 2.87-2.56 (m, 2H), 0.96-0.68 (m, 3H), 0.68-0.44 (m, 1H). LRMS (ESI) calcd for (C ₁₆ H ₂₂ N ₆ O + H ⁺ ) 315.2, found 315.2.

Example 59. 2- (1) H -Imidazol-1-yl) -1- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.20-6.96 (m, 3H) , 6.60 (d, J = 10.0 Hz, 1H), 5.60-5.35 (m, 1H), 4.75 (d, J = 6.7 Hz, 2H), 4.02-3.88 (m, 1H), 3.77 (dd, J = 27.1 , 10.8 Hz, 1H), 3.59-3.49 (m, 1H), 3.49-3.30 (m, 3H), 1.18-1.08 (m, 1H), 1.08-0.96 (m, 1H), 0.96-0.72 (m, 3H ). LRMS (ESI) calcd for (C ₁₈ H ₂₁ N ₇ O + H ⁺ ) 352.2, found 352.1.

Example 60. 3- (7- (Methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.35 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.16-7.07 (m, 1H), 6.58 (dd, J = 5.6, 3.7 Hz, 1H), 5.52 (ddd, J = 9.0, 7.3, 2.4 Hz, 1H), 4.44-4.20 (m, 2H), 4.11 (dd, J = 55.2, 12.4 Hz, 1H), 3.91 (d, J = 9.3 Hz , 2H), 3.73 (dd, J = 68.2, 12.8 Hz, 1H), 3.42 (d, J = 22.7 Hz, 3H), 1.18-1.01 (m, 1H), 0.98-0.75 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ S + H ⁺ ) 327.1, found 327.1.

Example 61. Isobutyl 7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (s, 1H), 8.24 (s, 1H), 7.05 (s, 1H), 6.59 (s, 1H), 5.40 (s, 1H), 4.04 (dd, J = 12.3, 7.5 Hz, 1H), 3.92 (d, J = 5.3 Hz, 2H), 3.85-3.62 (m, 2H), 3.51-3.23 (m, 4H), 2.05-1.86 (m, 1H), 1.13 -0.86 (m, 7H), 0.77 (d, J = 8.0 Hz, 3H). LRMS (ESI) calcd for (C ₁₈ H ₂₅ N ₅ 0 ₂ + H ⁺ ) 344.2, found 344.1.

Example 62. N -(5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.01 (s, 1H), 8.24 (s, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 5.57 (dd, J = 7.5, 3.1 Hz, 1H), 3.94 (dd, J = 11.0, 7.5 Hz, 1H), 3.74-3.64 (m, 2H), 3.55-3.47 (m, 3H), 3.36 (d, J = 9.8 Hz, 1H), 3.16-3.04 (m, 2H), 1.45 (t, J = 7.4 Hz, 3H), 1.10-1.03 (m, 1H), 0.86-0.71 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₂₁ N ₅ 0 ₂ S + H ⁺ ) 336.2, found 336.2.

Example 63. N -(5-((2-aminoethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.81 (s, 1H), 8.24 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 5.54 (dd, J = 7.4, 2.9 Hz, 1H), 3.92 (dd, J = 11.0, 7.6 Hz, 1H), 3.76-3.59 (m, 2H), 3.48 (s, 3H), 3.33 (d, J = 9.9 Hz, 1H), 3.30-3.22 (m, 2H), 3.22-3.02 (m, 2H), 1.88 (s, 2H), 1.04 (dd, J = 7.3, 4.2 Hz, 1H), 0.91-0.58 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₂₂ N ₆ O ₂ S + H ⁺ ) 351.2, found 351.2.

Example 64. S ) -1- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.49 (s, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 5.48-5.32 (m, 1H), 4.18-3.98 (m, 1H), 3.82 (ddd, J = 47.3, 32.5, 11.5 Hz, 2H), 3.51-3.28 (m, 4H), 2.32 (td, J = 14.9, 7.6 Hz, 2H) , 1.27 (d, J = 9.7 Hz, 1H), 1.22-1.11 (m, 2H), 1.11-0.93 (m, 1H), 0.93-0.61 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₂₁ N ₅ O + H ⁺ ) 300.2, found 300.1.

Example 65. S ) -2-azido-1- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethan-1-one

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 23.7 Hz, 1H), 6.66-6.45 (m, 1H) , 5.43 (dd, J = 47.4, 5.3 Hz, 1H), 4.15-4.01 (m, 1H), 3.99-3.74 (m, 3H), 3.58 (dd, J = 58.3, 11.9 Hz, 1H), 3.46-3.31 (m, 4H), 1.13-0.94 (m, 1H), 0.92-0.66 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₁₈ N ₈ O + H ⁺ ) 327.2, found 327.2.

Example 66. S ) -3- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.37 (s, 1H), 8.26 (d, J = 4.5 Hz, 1H), 7.16-7.02 (m, 1H), 6.57 (dd, J = 7.0, 3.5 Hz, 1H), 5.45 (ddd, J = 38.6, 7.3, 2.3 Hz, 1H), 4.14 (ddd, J = 21.4, 12.5, 7.5 Hz, 1H), 3.91 (t, J = 11.5 Hz, 1H), 3.85 (ddd , J = 13.7, 12.7, 2.6 Hz, 1H), 3.48 (q, J = 13.5 Hz, 1H), 3.45 (s, 3H), 3.39 (s, 2H), 1.14-0.98 (m, 1H), 0.92- 0.73 (m, 3 H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ O + H ⁺ ) 311.2, found 311.2.

Example 67. S )- N -Methyl-3- (7- (methyl (7 H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanamide

¹ H NMR (500 MHz, CDCl ₃ ) δ 11.85 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 11.0 Hz, 1H), 7.11 (d , J = 3.0 Hz, 1H), 6.55 (s, 1H), 5.43 (dd, J = 16.7, 6.3 Hz, 1H), 4.13 (ddd, J = 21.1, 12.5, 7.5 Hz, 1H), 4.00-3.81 ( m, 2H), 3.49 (t, J = 11.4 Hz, 1H), 3.40 (d, J = 18.6 Hz, 3H), 3.37 (d, J = 29.0 Hz, 2H), 2.86 (t, J = 11.0 Hz, 3H), 1.09-0.97 (m, 1 H), 0.86-0.69 (m, 3H). LRMS (ESI) calcd for (C ₁₇ H ₂₂ N ₆ O ₂ + H ⁺ ) 343.2, found 343.1.

Example 68. S ) -4- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (s, 1H), 8.24 (d, J = 27.2 Hz, 1H), 7.85-7.55 (m, 4H), 7.07 (d, J = 7.4 Hz, 1H) , 6.59 (d, J = 19.0 Hz, 1H), 5.64-5.34 (m, 1H), 4.37-4.03 (m, 2H), 3.84-3.27 (m, 5H), 1.16-1.00 (m, 1H), 0.98 -0.60 (m, 3 H). LRMS (ESI) calcd for (C ₂₁ H ₂₀ N ₆ O + H ⁺ ) 373.2, found 373.2.

Example 69. S ) -3- (7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.13 (s, 1H), 8.18 (s, 1H), 7.11-6.97 (m, 1H), 6.59-6.44 (m, 1H), 5.56-5.34 (m, 1H ), 4.38-3.92 (m, 3H), 3.92-3.78 (m, 2H), 3.66 (dd, J = 67.4, 13.0 Hz, 1H), 3.36 (d, J = 22.9 Hz, 3H), 1.09-0.94 ( m, 1H), 0.91-0.58 (m, 3H). LRMS (ESI) calcd for (C ₁₆ H ₁₈ N ₆ S + H ⁺ ) 327.1, found 327.1.

Example 70. Isobutyl ( S ) -7- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.26 (s, 1H), 8.25 (s, 1H), 7.07 (d, J = 3.2 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 5.51 -5.50 (m, 1H), 4.11-4.04 (m, 1H), 3.93 (d, J = 1.2 Hz, 2H), 3.91-3.74 (m, 2H), 3.42-3.38 (m, 4H), 2.01-1.90 (m, 1H), 1.01-0.95 (m, 7H), 0.77-0.75 (d, J = 10.0 Hz, 3H). LRMS (ESI) calcd for (C ₁₈ H ₂₅ N ₅ 0 ₂ + H ⁺ ) 344.2, found 344.3.

Example 71. S )- N -(5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, 1H), 8.23 (s, 1H), 7.07 (d, J = 3.1 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 5.55 (dd, J = 7.5, 3.0 Hz, 1H), 3.92 (dd, J = 11.0, 7.6 Hz, 1H), 3.80-3.57 (m, 2H), 3.48 (s, 3H), 3.33 (d, J = 9.8 Hz, 1H), 3.08 (q, J = 7.4 Hz, 2H), 1.43 (t, J = 7.4 Hz, 3H), 1.11-0.90 (m, 1H), 0.90-0.60 (m, 3H). LRMS (ESI) calcd for (C ₁₅ H ₂₁ N ₅ 0 ₂ S + H ⁺ ) 336.2, found 336.1.

Example 72. S )- N -methyl- N -(5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 8.16 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 6.9 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.04 (s, 1H), 6.53 (s, 1H), 5.46-5.36 (m, 1H), 3.68-3.56 (m, 2H), 3.52 (d, J = 9.6 Hz, 1H), 3.34 (s, 3H), 3.07 (d, J = 9.5 Hz, 1H), 0.93-0.83 (m, 1H), 0.78-0.68 (m, 1H), 0.65-0.55 (m, 2H) . LRMS (ESI) calcd for (C ₁₉ H ₂₁ N ₅ 0 ₂ S + H ⁺ ) 384.2, found 384.0.

Example 73. R )- N -(5-ethyl-5-azaspiro [2.4] heptan-7-yl)- N -Methyl-7 H -Pyrrolo [2,3- d ] Pyrimidin-4-amine

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 8.29 (s, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 5.57 (s, 1H), 3.47 (s, 3H), 3.16 (s, 1H), 3.03 (s, 1H), 2.92 (d, J = 7.6 Hz, 1H), 2.66 (d, J = 9.2 Hz, 3H) , 1.23 (t, J = 7.2 Hz, 3H), 0.98-0.94 (m, 1H), 0.77-0.68 (m, 2H), 0.55-0.53 (m, 1H). LRMS (ESI) calcd for (C ₁₅ H ₂₁ N ₅ + H ⁺ ) 272.2, found 272.1.

Example 74. R ) -3- (8- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -6-azaspiro [3.4] octan-6-yl) -3-oxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 8.32 (s, 1H), 7.09-7.06 (m, 1H), 6.63-6.61 (m, 1H), 5.99-5.92 (m, 1H ), 4.02-3.80 (m, 2H), 3.77-3.67 (m, 2H), 3.47 (d, J = 6.0 Hz, 2H), 3.27 (d, J = 4.8 Hz, 3H), 2.27-2.05 (m, 2H), 2.03-1.86 (m, 4H). LRMS (ESI) calcd for (C ₁₇ H ₂₀ N ₆ O + H ⁺ ) 325.2, found 325.1.

Example 75. S ) -3- (8- (methyl (7) H -Pyrrolo [2,3- d ] Pyrimidin-4-yl) amino) -6-azaspiro [3.4] octan-6-yl) -3-oxopropanenitrile

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (s, 1H), 8.32 (s, 1H), 7.08-7.06 (m, 1H), 6.63-6.61 (m, 1H), 5.99-5.92 (m, 1H ), 4.02-3.84 (m, 2H), 3.81-3.67 (m, 2H), 3.47 (d, J = 6.0 Hz, 2H), 3.27 (d, J = 4.8 Hz, 3H), 2.27-2.08 (m, 2H), 2.05-1.86 (m, 4H). LRMS (ESI) calcd for (C ₁₇ H ₂₀ N ₆ O + H ⁺ ) 325.2, found 325.1.

Example 76: Effect of Compounds of Formula 1 as JAK Inhibitors

1. In vitro phosphatase inhibition test method

(1) phosphatase dilution

Kinases were used as human-derived JAK1, JAK2, JAK3 and TYK2 (Millipore, Germany), diluted with the appropriate buffer for each enzyme described below and mixed with the reaction reagents.

(1.1) JAK1  Dilution Buffer  Furtherance

Dissolve tris (hydroxymethyl) aminomethane (TRIS) and ethylenediaminetetraacetic acid (EDTA) in distilled water to 20 mM and 0.2 mM, respectively, and 100 uL β-mer based on 100 mL. Captoethanol, 10 uL Brij-35 ^™ , and 5 mL glycerol were added to prepare JAK1 dilution buffer.

(1.2) JAK2, JAK3, and TYK2 Dilution Buffer Compositions

Dissolve 3-morpholinopropane-1-sulfonic acid (MOPS) and EDTA in distilled water to 20 mM and 1 mM, respectively, and 100 uL β-mercaptoethanol based on 100 mL, 10 uL Brij-35 ^™ , 5 mL glycerol and 100 mg BSA were added to prepare JAK2, JAK3, and TYK2 dilution buffers.

(2) Compound Preparation and Experimental Method

All compounds are dissolved at 50 uM concentration in 100% DMSO solution. The resulting solution was reacted with the reaction reagent in each well of a 96-well plate with a final concentration of 1 uM. Detailed test methods for each kinase are as follows.

(2.1) JAK1

The final concentration of the material contained in the reaction solution of 25 uL is shown in Table 1 below.

γ- ³³ P-ATP was prepared from non-radiolabeled ATP (Sigma, Cat. no. A-7699). After reacting for 40 minutes at room temperature, 5 uL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After the reaction, 10 uL of the solution was added to a GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed three times with 75 mM phosphate solution for 5 minutes. Methanol drying was performed and scintillation was measured. Methanol drying refers to the addition of methanol in an aqueous solution and drying using an azeotrope effect.

(2.2) JAK2

The final concentration of the material contained in the reaction solution of 25 uL is shown in Table 2 below.

γ- ³³ P-ATP was prepared from non-radiolabeled ATP (Sigma, Cat. no. A-7699). After reacting for 40 minutes at room temperature, 5 uL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After the reaction, 10 uL of the solution was added to a GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed three times with 75 mM phosphate solution for 5 minutes. Methanol drying was performed and scintillation was measured.

(2.3) JAK3

The final concentration of the material contained in the reaction solution of 25 uL is shown in Table 3 below.

γ- ³³ P-ATP was prepared from non-radiolabeled ATP (Sigma, Cat. no. A-7699). After reacting for 40 minutes at room temperature, 5 uL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After the reaction, 10 uL of the solution was added to a GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed three times with 75 mM phosphate solution for 5 minutes. Methanol drying was performed and scintillation was measured.

(2.4) TYK2

The final concentration of the material contained in the reaction solution of 25 uL is shown in Table 4 below.

γ- ³³ P-ATP was prepared from non-radiolabeled ATP (Sigma, Cat. no. A-7699). After reacting for 40 minutes at room temperature, 5 uL of 3 (v / v)% phosphoric acid solution was added to stop the reaction. After the reaction, 10 uL of the solution was added to a GF / P30 filtermat (PerkinElmer ^™ , 1450-523) and washed three times with 75 mM phosphate solution for 5 minutes. Methanol drying was performed and scintillation was measured.

(2.5) IC ₅₀  Measurement of values

For some compounds of Examples 1 to 75 (e.g., Examples 5, 55 and 66) at different concentrations, the inhibitory effect on JAK1, JAK2, JAK3 and TYK2 was measured according to the method described above and IC ₅₀ values were determined. Measured. IC ₅₀ values of the test compounds were calculated from each% inhibition value of the compound using the Chang-Furothor method (Biochem. Pharmacol. (1973) 22, 3099-3108).

(3) test result

Tables 5 and 6 show the results of measuring the extent to which the compounds synthesized in Examples 1 to 75 inhibit the phosphorylation activity of JAK1, JAK2, JAK3 and TYK2 according to the above-described method. Example numbers in Tables 5 and 6 represent the compounds synthesized in the examples, and the values of JAK1, JAK2, JAK3 and TYK2 columns indicate the degree of inhibition of the phosphorylation activity of these enzymes at the concentration of 1 uM of the compound synthesized in the example. Is expressed as a percentage. In Tables 5 and 6, negative values indicate substantially no inhibitory effect.

The degree of inhibition represents the reduced percentage of phosphorylation activity measured in the experimental group relative to the phosphorylation activity obtained in the negative control experiment without the compound.

% Inhibition = (Measurement value from test substance-treated group-Measurement value from test substance-treated group) / (Measurement value from test substance-treated group) x 100

As a control, 1 uM of Tofacitinib citrate (Hangzhou Tacon Co., Ltd.) was used and the inhibition rates for JAK1, JAK2, JAK3, and TYK2 were 99%, 98%, 99% and 100%, respectively.

Table 7 shows the IC ₅₀ for JAK1, JAK2, JAK3 and TYK2 activity of the compounds of Examples 5, 55, 66, 41, 62, and 74.

As shown in Table 7, the compound of Example 5 having an R-batch has about 3.5 times higher JAK1 inhibitory activity compared to the compound of Example 55, which is a racemic mixture thereof. Thus, by separating certain stereoisomers, such as enantiomers or diastereomers, which have a large inhibitory effect on JAK, it is possible to efficiently treat diseases associated with JAK.

2. Alopecia Therapeutic Effect Test in Hair Loss Mice

After shaving the back of 6-7 week-old C57BL / 6 mice in the resting state, the compound and HCl of Example 5 were applied to the skin for 15 days to confirm the extent of induction of growth.

Test group: negative control group (G1), 3% compound of Example 5, HCl (G2), and 3% Minoxidil (G3)

The negative control group G1 is sterile water for injection, and the G2 and G3 solutions are solutions with sterile water for injection.

As an experimental result, Figure 1 is a diagram showing the effect of the compound of formula 1 on hair growth in the hair loss model mouse. 1 is a graph showing the result of measuring the area of the hair growth part on a designated date. As shown in Figure 1, the compound · HCl of Example 5 showed a significant hair production effect compared to the control. In FIG. 1, * represents p <0.05 and n = 4.

From the above results, it was confirmed that the compound of formula 1 has an effect of preventing hair loss or promoting hair growth.

Claims (17)

1. As a compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof,

   

    (Formula 1)

   Wherein R ¹ is C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl,

   R ² and R ³ together are - (C _{2 -6} alkyl) -, or form -, - (C _{2 -6} alkenyl)

   R ⁴ is -W ¹ -R ⁶ ;

   W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -, -S (= 0)-, or -S (= 0) _2- ;

   R ⁵ is H or C _1-6 alkyl;

   R ⁶ is H; Halo; CN; NO ₂ ; N ₃ ; C _1-10 alkyl: C _2-10 alkenyl; C _2-10 alkynyl; C _1-6 haloalkyl; C _5-20 aryl optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ , and —O— (C _1-10 alkyl). ; C _3-7 cycloalkyl; Heterocycloalkyl having 3 to 7 ring atoms, optionally substituted with —C ( _C═O ) (C _1-6 alkyl); Heteroaryl having 3 to 7 ring atoms; Heteroaryl- ( _{Ci_ 10} alkyl) having 3 to 7 ring atoms; -(Ci_ ₁₀ alkyl) -CN; -( _{Ci_ 10} alkyl) -N ₃ ; -(C _1-10 alkyl) -O- (C _1-6 alkyl); — (C _1-10 alkyl) -C (═O) NR ^a R ^b ; Or-(C _1-10 alkyl) -NR ^a C (= 0) R ^b or-(C _1-10 alkyl) -NR ^c R ^d , wherein R ^a , R ^b , R ^c , and R ^d are mutually Hair loss in mammals comprising as an active ingredient a compound of Formula 1, or a pharmaceutically, cosmetically or food acceptable salt or solvate or stereoisomer thereof, which is independently H or C _1-6 alkyl A composition for preventing or promoting hair growth.
2. The composition of claim 1, wherein the compound of Formula 1 is wherein R ¹ is C _1-6 alkyl and R ² and R ³ together form — (C _2-6 alkyl) —.
3. 2. The compound of formula 1, wherein W ¹ is absent from the corresponding atom, or is —C (═O) —, —C (═S) —, —C (═O) O—, —C (═O) NR ^5. -, -C (= S) NR ^5- , or -S (= 0) _2- ; R ⁵ is H or C _1-6 alkyl;

   R ⁶ is C _1-10 alkyl; C _1-6 haloalkyl; C _5-20 aryl optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ , and —O— (C _1-10 alkyl). ; C _3-7 cycloalkyl; Heterocycloalkyl having 3 to 7 ring atoms, optionally substituted with —C ( _C═O ) (C _1-6 alkyl); Heteroaryl having 3 to 7 ring atoms; _-Heteroaryl- ( _{Ci_ 10} alkyl) having 3 to 7 ring atoms; -(Ci_ ₁₀ alkyl) -CN; -( _{Ci_ 10} alkyl) -N ₃ ; -(C _1-10 alkyl) -O- (C _1-6 alkyl); — (C _1-10 alkyl) -C (═O) NR ^a R ^b ; Or-(C _1-10 alkyl) -NR ^a C (= 0) R ^b or-(C _1-10 alkyl) -NR ^c R ^d , wherein R ^a , R ^b , R ^c , and R ^d are mutually Independently H or C _1-6 alkyl.
4. The compound of claim 1, wherein the compound of Formula 1 has the general formula of Formula 2,

   

    (Formula 2)

   R ⁴ in formula 2 is -W ¹ -R ⁶ ;

   W ¹ is absent or -C (= O)-, -C (= S)-, -C (= O) O-, -C (= O) NR ^5- , -C (= S) NR ⁵ -Or -S (= 0) _2- ;

   R ⁵ is H or C _1-6 alkyl;

   R ⁶ is

   When W ¹ is absent, it is C _1-10 alkyl,

   When W ¹ is —C (═O) —, C _1-10 alkyl; C _3-7 cycloalkyl; -(Ci_ ₁₀ alkyl) -CN; -( _{Ci_ 10} alkyl) -N ₃ ; R ^a and R ^b are each independently H or C _1-6 alkyl-(C _1-10 alkyl) -NR ^a C (═O) R ^b ; R ^a and R ^b are independently of each other H or C _1-6 alkyl-(C _1-10 alkyl) -C (═O) NR ^a R ^b ; Phenyl; -CF ₃ , and phenyl substituted with one or more substituents selected from the group consisting of CN; Piperidinyl substituted with —C ( _C═O ) (C _1-6 alkyl); Furanyl; Pyridinyl; Imidazolyl- (Ci_ ₁₀ alkyl); -(C _1-10 alkyl) -O- (C _1-6 alkyl); Or R ^c and R ^d are each independently H or C _1-6 alkyl-(C _1-10 alkyl) -NR ^c R ^d ,

   When W ¹ is -C (= S)-,-(C _1-10 alkyl) -CN,

   When W ¹ is —C (═O) O—, it is — (C _1-10 alkyl),

   When W ¹ is -C (= 0) NR ⁵ ,-(C _1-10 alkyl); C _3-7 cycloalkyl; Phenyl; Halo, and phenyl substituted with one or more substituents selected from the group consisting of C _1-10 alkyl; Biphenyl; Or biphenyl substituted with one or more substituents selected from the group consisting of halo and C _1-10 alkyl,

   When W ¹ is -C (= S) NR ⁵ , it is phenyl substituted with one or more -CF ₃ ,

   When W ¹ is —S (═O) ₂ —, —C _1-10 alkyl; -CF ₃ ; Piperidinyl; Morpholinyl; R ^c and R ^d are each independently H or C _1-6 alkyl-(C _1-10 alkyl) -NR ^c R ^d ; Phenyl; Phenyl substituted with one or more substituents independently selected from-(C _1-10 alkyl), -O- (C _1-6 alkyl), -CF ₃ , NO ₂ , CN, and halo; Naphthalenyl; Or naphthal substituted with one or more substituents independently selected _from- (C _1-10 alkyl), -O- (C _1-6 alkyl),-(C _1-6 haloalkyl), NO ₂ , CN, and halo Reenyl.
5. The compound of claim 1 wherein

   (R) -N- (5-butyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine;

   (R) -N-methyl-N- (5-pentyl-5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine;

   (R) -2-methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) Propane-1-one;

   (R) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl ) Ethan-1-one;

   (R) -3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxo Propanenitrile;

   (R) -3-methyl-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) Butan-1-one;

   (R) -N- (2- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl)- 2-oxoethyl) acetamide;

   (R) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) 3-oxopropanamide;

   (R) -cyclopropyl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methanone;

   (R) -1- (4- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) Piperidin-1-yl) ethan-1-one;

   (R) -furan-2-yl (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) methane On;

   (R)-(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-3-yl Methanone;

   (R)-(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (phenyl) methanone;

   (R)-(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (pyridin-4-yl Methanone;

   (R) -3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile;

   (R) -4- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile;

   (R)-(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (2- (trifluoro Romethyl) phenyl) methanone;

   (R)-(7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) (3- (trifluoro Romethyl) phenyl) methanone;

   (R) -3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thi Oxopropanenitrile;

   Isobutyl (R) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate;

   (R) -N-butyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide;

   (R) -N-cyclohexyl-7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxamide;

   (R) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -N-phenyl-5-azaspiro [2.4] heptan-5-carboxamide;

   (R) -N- (4-fluorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5 Carboxamides;

   (R) -N- (2,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane- 5-carboxamide;

   (R) -N- (3,4-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane- 5-carboxamide;

   (R) -N- (2,5-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane- 5-carboxamide;

   (R) -N- (2,3-dichlorophenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane- 5-carboxamide;

   (R) -N- (3-chloro-4-methylphenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-carboxamide;

   (R) -N-([1,1'-biphenyl] -2-yl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5- Azaspiro [2.4] heptan-5-carboxamide;

   (R) -N- (3,5-bis (trifluoromethyl) phenyl) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-aza Spiro [2.4] heptan-5-carbothioamide;

   (R) -N-methyl-N- (5-((trifluoromethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrid Midin-4-amine;

   (R) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine ;

   (R) -N- (5- (isopropylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine-4- Amines;

   (R) -N-methyl-N- (5- (propylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ;

   (R) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ;

   (R) -N- (5-((2-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] Pyrimidin-4-amine;

   (R) -N- (5-((3-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] Pyrimidin-4-amine;

   (R) -N- (5-((4-fluorophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] Pyrimidin-4-amine;

   (R) -2-((7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) Benzonitrile;

   (R) -3-((7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) Benzonitrile;

   (R) -4-((7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) sulfonyl) Benzonitrile;

   (R) -N-methyl-N- (5-((2-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrid Midin-4-amine;

   (R) -N-methyl-N- (5-((3-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrid Midin-4-amine;

   (R) -N-methyl-N- (5-((4-nitrophenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrid Midin-4-amine;

   (R) -N-methyl-N- (5- (m-tolylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4 Amines;

   (R) -N- (5-((4-methoxyphenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] Pyrimidin-4-amine;

   (R) -N-methyl-N- (5-((4- (trifluoromethyl) phenyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-amine;

   (R) -N-methyl-N- (5- (naphthalen-2-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine- 4-amine;

   (R) -N-methyl-N- (5- (piperidin-1-ylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrid Midin-4-amine;

   (R) -N-methyl-N- (5- (morpholinosulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidine-4- Amines;

   1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propan-1-one;

   2-methoxy-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane-1 -On;

   2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) ethane-1 -On;

   3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxopropanenitrile;

   N- (2- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -2-oxoethyl Acetamide;

   N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxo Propanamide;

   3-amino-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propane-1- On;

   2- (1H-imidazol-1-yl) -1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptane -5-yl) ethan-1-one;

   3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-thioxopropanenitrile;

   Isobutyl 7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate;

   N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine;

   N- (5-((2-aminoethyl) sulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidine-4- Amines;

   (S) -1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) propane-1- On;

   (S) -2-azido-1- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl ) Ethan-1-one;

   (S) -3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-oxo Propanenitrile;

   (S) -N-methyl-3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) 3-oxopropanamide;

   (S) -4- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carbonyl) benzonitrile;

   (S) -3- (7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-yl) -3-ti Oxopropanenitrile;

   Isobutyl (S) -7- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -5-azaspiro [2.4] heptan-5-carboxylate;

   (S) -N- (5- (ethylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine ;

   (S) -N-methyl-N- (5- (phenylsulfonyl) -5-azaspiro [2.4] heptan-7-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ;

   (R) -N- (5-ethyl-5-azaspiro [2.4] heptan-7-yl) -N-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine;

   (R) -3- (8- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -6-azaspiro [3.4] octan-6-yl) -3-oxo Propanenitrile; or

   (S) -3- (8- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -6-azaspiro [3.4] octan-6-yl) -3-oxo The composition is propanenitrile.
6. The composition of claim 1, wherein the compound of formula 1 inhibits JAK-STAT signaling.
7. The composition of claim 1, which is a pharmaceutical, cosmetic, or food composition.
8. The composition of claim 1 for treating alopecia.
9. The method according to claim 8, wherein the alopecia is alopecia areata, androgenetic alopecia, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, circumscribed alopecia, alopecia congenitalis, alopecia pubis, seborrheic alopecia (alopecia seborrheica), alopecia senilis, alopecia totalis, alopecia universalis, alopecia universal hair loss (anagen effluvium) ), Telogen effluvium, stress alopecia, female pattern alopecia, or male pattern alopecia.
10. The method of claim 1, further comprising: subcutaneous, intramuscular, intraperitoneal or intravenous injection; Injection; A formulation for use in oral, nasal or topical application.
11. The composition of claim 1, wherein the formulation for use in topical application is a formulation for application to the skin including the scalp.
12. The pharmaceutical composition of claim 1, wherein the formulation is a cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma formulation.
13. The method according to claim 1, hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisturizing cream, hair massage cream, hair wax, hair Aerosols, hair packs, hair nutrition packs, hair soaps, hair cleansing foams, hair oils, hair dryers, hair preservatives, hair colorants, hair wave agents, hair bleaches, hair gels, hair glazes, hairdressers, hair lacquers, hair moisturizers , Cosmetic composition of the formulation of hair mousse, eyebrow nutrients, eyelash nutritional or hairspray.
14. A method of preventing hair loss or promoting hair growth of an individual, comprising administering the pharmaceutical composition to the mammalian subject of claim 1.
15. The method of claim 14, wherein administering comprises applying the composition to the skin.
16. The method of claim 15, wherein the skin is human scalp.
17. The method of claim 15, for treating alopecia.

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