JP6367545B2 - Deuterated derivatives of ruxolitinib - Google Patents

Description

  The present invention relates to deuterated derivatives of ruxolitinib.

BACKGROUND OF THE INVENTION Many current drugs have the disadvantages of poor absorption, distribution, metabolism and / or excretion (ADME) properties that prevent their widespread use or limit their use in certain indications. Also, poor ADME properties are mainly due to lack of drug candidates in clinical trials. Formulation techniques and prodrug strategies can be used in some cases to improve specific ADME properties, but these approaches often address the underlying ADME challenges that exist for many drugs and drug candidates It has failed. One such challenge is the rapid metabolism that many drugs are removed from the body too quickly, otherwise very effective in treating the disease. A possible solution for rapid drug clearance is frequent or frequent dosing to achieve sufficiently high plasma levels of the drug. However, this leads to a number of potential therapeutic challenges, such as poor patient compliance with dosing regimens, side effects that become more severe with increasing dosage and increased cost of treatment. Also, rapidly metabolized drugs can expose patients to undesirable toxic or reactive metabolites.

  Another ADME limitation that affects many drugs is the formation of toxic or biologically reactive metabolites. As a result, some patients who receive drugs may experience toxicity, or the safe dosing of such drugs may be limited so that patients receive suboptimal active agents . In some cases, altering the dosing interval or formulation approach can help reduce clinical adverse effects, but often the formation of such undesirable metabolites is inherent in the metabolism of the compound.

  In some cases, metabolic inhibitors are co-administered with drugs that are removed very quickly. This is the case with the protease inhibitor class of drugs used to treat HIV infection. The FDA recommends co-administering these drugs with ritonavir, an inhibitor of the cytochrome P450 enzyme 3A4 (CYP3A4), an enzyme that is typically responsible for drug metabolism (Kempf, DJ et al., Antimicrobial agents and chemotherapy, 1997, 41 (3): 654-60). However, ritonavir adversely affects HIV patients who must have previously taken a combination of different drugs and adds pill burden. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan to reduce the rapid CYP2D6 metabolism of dextromethorphan in the treatment of pseudomedullary palsy. However, quinidine has undesirable side effects that greatly limit its use in potential combination therapy (Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56 (6 Pt 1): 659-67 and www.accessdata (See the FDA label for quinidine in .fda.gov).

  In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for reducing drug clearance. Inhibition of the activity of the CYP enzyme can affect the metabolism and clearance of other drugs that are metabolized by the same enzyme. CYP inhibition causes other drugs to accumulate in the body to toxic levels.

  A potentially attractive strategy for improving the metabolic properties of drugs is deuteration modification. In this approach, certain attempts are made to retard CYP-mediated metabolism of drugs or reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe and stable non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms a stronger bond with carbon. In selective cases, the increased bond strength imparted by deuterium can positively affect the ADME properties of the drug, creating the possibility for improved drug efficacy, safety and / or tolerability. At the same time, since the size and shape of deuterium is essentially the same as that of hydrogen, the replacement of hydrogen with deuterium is the biochemical ability and choice of the drug compared to the entire original compound containing only hydrogen. It is not expected to affect sex.

  Over the past 35 years, the effect of deuterium substitution on the rate of metabolism has been reported in a very low proportion of approved drugs (e.g. Blake, MI et al, J Pharm Sci, 1975, 64: 367-91 Foster, AB, Adv Drug Res 1985, 14: 1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006 , 9: 101-09 ("Fisher")). Many of the examples in these references are more detrimental than the effects of deuteration on the overall metabolic stability of the drug, i.e., the overall substrate consumption through metabolism (the deuterium isotope effect at a particular site). Report the effect of hydrogenation on metabolic rate). The reported results of these studies measuring the effect of deuterium substitution on metabolic stability are variable and unpredictable. For some compounds, deuteration caused a decrease in metabolic clearance in vivo. There was no metabolic change for the others. Still others showed increased metabolic clearance. The variability in the deuterium effect also caused questions or disclaimer to those skilled in the art about deuterium modification as a feasible drug design strategy for inhibition of poor metabolism (Foster p. 35 and Fisher p. 101).

  The effect of deuterium modification on the metabolic properties of a drug cannot be predicted even if deuterium atoms are incorporated into known sites of metabolism. Only by actually preparing and testing a deuterated drug can it be determined whether and how the metabolic rate differs from the non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism can occur. The sites where deuterium substitution is required and the degree of deuteration needed to see the effect on metabolism, if any, will vary for each drug.

  Ruxolitinib phosphate is 3 (R) -cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanenitrile phosphate Salt and heterogeneous known as (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile phosphate Aryl-substituted pyrrolo [2,3-d] pyrimidine, which inhibits Janus related kinase (JAK), JAK1 and JAK2. These kinases mediate the signaling of many cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling is involved in the subsequent nuclear localization leading to the association of STATs (signal transducers and activators of transcription) to cytokine receptors, activation of STATs and regulation of gene expression To do.

  Ruxolitinibrate is currently for the treatment of patients with moderate or high risk myelofibrosis, such as primary myelofibrosis, post-erythrocytic myelofibrosis, and essential post-thrombocytopenic myelofibrosis Has been approved. Ruxolitinib phosphate is also currently in clinical trials for the treatment of essential thrombocytopenia, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma and psoriasis.

  In humans, three metabolites of ketones identified as active due to hydroxylation of the 2-position of the cyclopentyl moiety, those resulting from hydroxylation of the 3-position of the cyclopentyl moiety, and those resulting from further oxidation of the 3-position of the cyclopentyl moiety have been identified as active. ing. (See Shilling, A.D. et al., Drug Metabolism and Disposition, 2010, 38 (11): 2023-2031; FDA Prescribing Information and US20080312258).

  The most common hematopoietic adverse reactions associated with dosing with ruxolitinib are thrombocytopenia and anemia. The most common non-hematopoietic adverse reactions are bruising, dizziness and headache.

US20080312258

Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41 (3): 654-60 Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56 (6 Pt 1): 659-67 FDA label for quinidine at www.accessdata.fda.gov Blake, MI et al, J Pharm Sci, 1975, 64: 367-91 Foster, AB, Adv Drug Res 1985, 14: 1-40 Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88 Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 Fukuto et al. J. Med. Chem. 1991, 34, 2871-76 Shilling, A.D. et al., Drug Metabolism and Disposition, 2010, 38 (11): 2023-2031

  Despite the beneficial activity of ruxolitinib, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

の化合物またはその薬学的に許容され得る塩であって、
Y⁶、Y⁷およびY⁸は、それぞれ水素であり、該化合物は、以下の表：

に示される化合物(Cmpd)のいずれか1つより選択され、
重水素であるとは指定されない任意の原子がその天然の同位体存在度で存在する、化合物またはその薬学的に許容され得る塩、
〔２〕式I：

の化合物またはその薬学的に許容され得る塩であって、
Y⁶、Y⁷およびY⁸は、それぞれ重水素であり、該化合物は、以下の表：

に示される化合物(Cmpd)のいずれか1つより選択され、
重水素であるとは指定されない任意の原子がその天然の同位体存在度で存在する、化合物またはその薬学的に許容され得る塩、
〔３〕前記〔１〕記載の化合物および薬学的に許容され得る担体を含む、医薬組成物、
〔４〕前記〔２〕記載の化合物および薬学的に許容され得る担体を含む、医薬組成物、
〔５〕化合物127,

および薬学的に許容され得る担体を含む、医薬組成物、
〔６〕レナリドマイド、パノビノスタット、カペシタビン、エキセメスタンおよびそれらの組み合わせから選択される治療剤をさらに含む、前記[３]、[４]または〔５〕記載の組成物、
〔７〕 前記〔１〕もしくは〔２〕記載の化合物、またはそれらの薬学的に許容され得る塩を含む、細胞におけるJAK1またはJAK2の1つ以上の活性を阻害するための医薬組成物、
〔８〕化合物127:

またはその薬学的に許容され得る塩を含む、細胞におけるJAK1またはJAK2の1つ以上の活性を阻害するための医薬組成物、
〔９〕骨髄線維症、膵臓癌、前立腺癌、乳癌、白血病、非ホジキンリンパ腫、多発性骨髄腫、乾癬またはそれらの組み合わせを治療するための、前記〔３〕〜〔５〕いずれかに記載の医薬組成物、
〔１０〕骨髄線維症が、原発性骨髄線維症、真性赤血球増加症後骨髄線維症、本態性血小板減少後骨髄線維症、本態性血小板減少症またはそれらの組み合わせである、前記〔９〕記載の医薬組成物、
〔１１〕前記〔３〕〜〔５〕いずれか記載の医薬組成物ならびにレナリドマイド、パノビノスタット、カペシタビン、エキセメスタンおよびそれらの組み合わせから選択される治療剤を含む、骨髄線維症、膵臓癌、前立腺癌、乳癌、白血病、非ホジキンリンパ腫、多発性骨髄腫、乾癬またはそれらの組み合わせを治療するための組み合わせ医薬
に関する。 That is, the gist of the present invention is as follows.
[1] Formula I:

Or a pharmaceutically acceptable salt thereof,
Y ⁶ , Y ⁷ and Y ⁸ are each hydrogen and the compounds are represented in the following table:

Selected from any one of the compounds shown in (Cmpd),
A compound, or a pharmaceutically acceptable salt thereof, in which any atom not designated as deuterium is present in its natural isotopic abundance,
[2] Formula I:

Or a pharmaceutically acceptable salt thereof,
Y ⁶ , Y ⁷ and Y ⁸ are each deuterium and the compounds are represented in the following table:

Selected from any one of the compounds shown in (Cmpd),
A compound, or a pharmaceutically acceptable salt thereof, in which any atom not designated as deuterium is present in its natural isotopic abundance,
[3] A pharmaceutical composition comprising the compound according to [1] above and a pharmaceutically acceptable carrier,
[4] A pharmaceutical composition comprising the compound of [2] above and a pharmaceutically acceptable carrier,
[5] Compound 127,

And a pharmaceutical composition comprising a pharmaceutically acceptable carrier,
[6] The composition described in [3], [4] or [5] above, further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof,
[7] A pharmaceutical composition for inhibiting one or more activities of JAK1 or JAK2 in a cell, comprising the compound according to [1] or [2], or a pharmaceutically acceptable salt thereof,
[8] Compound 127:

Or a pharmaceutical composition for inhibiting one or more activities of JAK1 or JAK2 in a cell, comprising a pharmaceutically acceptable salt thereof,
[9] The method according to any one of [3] to [5] above for treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriasis, or a combination thereof. Pharmaceutical composition,
[10] The aforementioned [9], wherein the myelofibrosis is primary myelofibrosis, post-erythrocytic myelofibrosis, post-essential thrombocytopenia myelofibrosis, essential thrombocytopenia, or a combination thereof Pharmaceutical composition,
[11] Myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, comprising the pharmaceutical composition according to any one of [3] to [5] above and a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof , To a combination medicament for treating leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriasis or combinations thereof.

  According to the present invention, novel compounds for treating the aforementioned diseases and conditions can be provided.

FIG. 1 shows the results of metabolic stability studies of the referenced compounds.

Summary of the Invention The present invention relates to novel heteroaryl substituted pyrrolo [2,3-d] pyrimidines and pharmaceutically acceptable salts thereof. The present invention also relates to compositions comprising compounds of the present invention and methods of treating diseases and conditions that are advantageously treated by administration of inhibitors of Janus related kinases that are selective for subtypes 1 and 2 (JAK1 / JAK2). Use of such a composition is provided.

DETAILED DESCRIPTION OF THE INVENTIONDefinitions The term `` treatment '' refers to a reduction in the onset or progression of a disease (e.g., a disease or disorder shown herein), suppression, reduction, reduction, restraint or stabilization, reduction in disease severity, Or the improvement of the symptom relevant to the disease is meant.

  “Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

  It is understood that some changes in natural isotopic abundance occur in the synthesized compounds, depending on the origin of the chemicals used in the synthesis. Thus, the formulation of ruxolitinib contains essentially a small amount of deuterated isotopologue. The concentration of naturally occurring stable hydrogen and carbon isotopes is negligible in small amounts compared to the degree of stable isotope substitution of the compounds of the present invention, regardless of this change. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

  In the compounds of the present invention, no atom is specifically designated as a particular isotope, but is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, it is understood that the position has hydrogen at the natural abundance of the isotopic composition. Also, unless otherwise noted, when a position is specifically designated as “D” or “deuterium”, that position is at least 3000 times the natural abundance of deuterium, which is 0.015%. It is understood that deuterium has a high abundance (ie, at least 45% uptake of deuterium).

  As used herein, the term “isotopic enrichment factor” means the ratio between the isotopic abundance and the natural abundance of a particular isotope.

  In other embodiments, the compounds of the present invention have, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium uptake), at least 5500 (82.5% deuterium uptake), at least 6000 (90% deuterium uptake), at least 6333.3 (95% deuterium uptake), at least It has an isotopic enrichment factor of 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake), or at least 6633.3 (99.5% deuterium uptake).

  The term “isotopologue” refers to a species whose chemical structure differs from a particular compound of the invention only in its isotopic composition.

  The term “compound”, when referring to a compound of the present invention, refers to a collection of molecules having the same chemical structure, except where there may be isotopic variations in the constituent elements of the molecule. Thus, a compound represented by a particular chemical structure containing the indicated deuterium atom also includes a lower amount of isotopologue having a hydrogen atom at one or more of the designated deuterium positions in the structure. It will be apparent to those skilled in the art. The relative amount of such isotopologues in the compounds of the present invention is dependent on the isotopic purity of the deuterated reagent used to make the compound and the deuterium incorporation in the various synthetic steps used to prepare the compound. Depends on several factors such as efficiency. However, as mentioned above, the relative amount of such isotopologues as a whole is less than 49.9% in the compound. In other embodiments, the relative amount of such isotopologues as a whole is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, 3% in the compound. Less than, less than 1%, or less than 0.5%.

  The present invention also provides salts of the compounds of the present invention. Salts of the compounds of the present invention are formed between an acid and a basic group of the compound such as an amino functional group, or a base and an acidic group of the compound such as a carboxyl group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

  As used herein, the term “pharmaceutically acceptable” refers to humans and other mammals without causing excessive toxicity, irritation, allergic reactions, etc. within the scope of sound medical judgment. A component that is suitable for use in contact with other tissues and has a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that can provide a compound of the present invention, either directly or indirectly, upon administration to a recipient. A “pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

  Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and P-Toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid , Organic acids such as parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate. , Pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate , Oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloro Benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropiate Onnate, phenylbutyrate, citrate, lactate, β-hydroxylactate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, Naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, particularly those formed with organic acids such as maleic acid.

  Compounds of the invention (eg, compounds of formula I or formula A) may contain asymmetric carbon atoms, for example as a result of deuterium substitution or otherwise. Thus, the compounds of the present invention may exist as either individual enantiomers or as a mixture of two enantiomers. Accordingly, the compounds of the present invention may exist as either racemic mixtures or scalemic mixtures or as individual respective stereoisomers substantially free of other possible stereoisomers. The term “substantially free of other stereoisomers” as used herein is less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably other. Means that less than 5% of the other stereoisomers are present, most preferably less than 2% of the other stereoisomers. Methods for obtaining or synthesizing individual enantiomers for a given compound are known in the art and can be applied as practical to the final compound or starting material or intermediate.

  Unless otherwise indicated, when a disclosed compound is named or designated by structure without specifying stereochemistry and has one or more chiral centers, all possible stereoisomers of the compound are It is understood to show.

  As used herein, the term “mammal” includes a human or non-human animal, such as a mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon or rhesus monkey. It is done. In one embodiment, the mammal is a non-human animal. In another embodiment, the mammal is a human.

  As used herein, the term “stable compounds” refers to compounds that have sufficient stability to allow their manufacture and the purposes detailed herein (e.g., to therapeutic products). Formulation, intermediates for use in the manufacture of therapeutic compounds, preparation of isolatable or storable intermediate compounds, treatment of diseases or conditions responsive to therapeutic agents) for a sufficient period of time Refers to a compound that maintains

  Both “D” and “d” refer to deuterium. “Stereoisomer” refers to both enantiomers and diastereomers. “Tert” and “t-” refer to the third place. “US” refers to the United States.

  “Substituted with deuterium” means that one or more hydrogen atoms have been replaced with the corresponding number of deuterium atoms.

Throughout this specification, variants may be referred to generally (eg, “each R”) or specifically mentioned (eg, R ¹ , R ² , R ^3, etc.). Unless otherwise indicated, when a variant is generally referred to, it is meant to include all specific aspects of the particular variant.

(式中、
Y¹は、水素および重水素から選択され；
各Y²は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y²は同じものであるとし；
各Y³は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y³は同じものであるとし；
Y⁴は、水素および重水素から選択され；
各Y⁵は、同じであり、水素および重水素から選択され；
Y⁶、Y⁷、Y⁸、Y⁹およびY¹⁰は、それぞれ独立して水素および重水素から選択され；
ただし、Y¹が水素であり、各Y²および各Y³が水素であり、Y⁴が水素であり、Y⁶、Y⁷、Y⁸、Y⁹およびY¹⁰のそれぞれが水素である場合、各Y⁵は重水素である）
の化合物、またはその薬学的に許容され得る塩を提供する。 Therapeutic Compounds In one embodiment, the Formula A of the present invention:

(Where
Y ¹ is selected from hydrogen and deuterium;
Each Y ² is independently selected from hydrogen and deuterium, provided that each Y ² bonded to a common carbon is the same;
Each Y ³ is independently selected from hydrogen and deuterium, provided that each Y ³ bonded to a common carbon is the same;
Y ⁴ is selected from hydrogen and deuterium;
Each Y ⁵ is the same and is selected from hydrogen and deuterium;
Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ and Y ¹⁰ are each independently selected from hydrogen and deuterium;
However, when Y ¹ is hydrogen, each Y ² and each Y ³ are hydrogen, Y ⁴ is hydrogen, and each of Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ and Y ¹⁰ is hydrogen, Each Y ⁵ is deuterium)
Or a pharmaceutically acceptable salt thereof.

In one embodiment of Formula A, each Y ² is the same, each Y ³ is the same, and each Y ⁵ is the same. In one aspect of this embodiment, each Y ² is deuterium. In a further aspect, each Y ³ is deuterium. In another further aspect, each Y ³ is hydrogen. In another aspect of this embodiment, each Y ² is hydrogen. In a further aspect, each Y ³ is deuterium. In another further aspect, each Y ³ is hydrogen. In one example of any of the foregoing aspects, Y ¹ is deuterium. In another example of any of the foregoing aspects, Y ¹ is hydrogen. In more specific examples of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is deuterium, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is deuterium, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is hydrogen, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is hydrogen, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is hydrogen, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is deuterium, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is deuterium, and each Y ⁵ is hydrogen.

In one embodiment, Y ⁶ is deuterium. In one aspect of this embodiment, each of Y ⁷ and Y ⁸ is deuterium. In another aspect of this embodiment, each of Y ⁷ and Y ⁸ is hydrogen.

In one embodiment, Y ⁶ is hydrogen. In one aspect of this embodiment, each of Y ⁷ and Y ⁸ is deuterium. In another aspect of this embodiment, each of Y ⁷ and Y ⁸ is hydrogen.

(式中、
Y¹は水素および重水素から選択され；
各Y²は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y²は同じものであるとし；
各Y³は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y³は同じものであるとし；
Y⁴は水素および重水素から選択され；
各Y⁵は同じものであり、水素および重水素から選択され；
Y⁶、Y⁷およびY⁸は、それぞれ独立して水素および重水素から選択され；
ただし、Y¹が水素であり、各Y²および各Y³が水素であり、Y⁴が水素であり、Y⁶、Y⁷およびY⁸のそれぞれが水素である場合、各Y⁵は重水素である)
の化合物、またはその薬学的に許容され得る塩を提供する。 In one aspect, the invention provides a compound of formula I:

(Where
Y ¹ is selected from hydrogen and deuterium;
Each Y ² is independently selected from hydrogen and deuterium, provided that each Y ² bonded to a common carbon is the same;
Each Y ³ is independently selected from hydrogen and deuterium, provided that each Y ³ bonded to a common carbon is the same;
Y ⁴ is selected from hydrogen and deuterium;
Each Y ⁵ is the same and is selected from hydrogen and deuterium;
Y ⁶ , Y ⁷ and Y ⁸ are each independently selected from hydrogen and deuterium;
However, when Y ¹ is hydrogen, each Y ² and each Y ³ are hydrogen, Y ⁴ is hydrogen, and each of Y ⁶ , Y ⁷ and Y ⁸ is hydrogen, each Y ⁵ is deuterium Is)
Or a pharmaceutically acceptable salt thereof.

In one embodiment, each Y ² is the same, each Y ³ is the same, and each Y ⁵ is the same. In one aspect of this embodiment, each Y ² is deuterium. In a further aspect, each Y ³ is deuterium. In another further aspect, each Y ³ is hydrogen. In another aspect of this embodiment, each Y ² is hydrogen. In a further aspect, each Y ³ is deuterium. In another further aspect, each Y ³ is hydrogen. In one example of any of the foregoing aspects, Y ¹ is deuterium. In another example of any of the foregoing aspects, Y ¹ is hydrogen. In more specific examples of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is deuterium, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is deuterium, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is deuterium, Y ⁴ is hydrogen, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is hydrogen, and each Y ⁵ is hydrogen. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is hydrogen, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is deuterium, and each Y ⁵ is deuterium. In another more specific example of any of the foregoing aspects, Y ¹ is hydrogen, Y ⁴ is deuterium, and each Y ⁵ is hydrogen.

In one embodiment, Y ⁶ is deuterium. In one aspect of this embodiment, each of Y ⁷ and Y ⁸ is deuterium. In another aspect of this embodiment, each of Y ⁷ and Y ⁸ is hydrogen.

In one embodiment, Y ⁶ is hydrogen. In one aspect of this embodiment, each of Y ⁷ and Y ⁸ is deuterium. In another aspect of this embodiment, each of Y ⁷ and Y ⁸ is hydrogen.

に記載される化合物(Cmpd)のいずれか1つから選択されるか、またはそれらの薬学的に許容され得る塩であり、重水素と指定されない任意の原子は、その天然の同位体存在度で存在する。 In one embodiment, the compound is a compound of formula I wherein Y ⁶ , Y ⁷ and Y ⁸ are each hydrogen, and the compound is Table 1 (below):

Any atom selected from any one of the compounds described in (Cmpd) or a pharmaceutically acceptable salt thereof and not designated as deuterium is in its natural isotopic abundance. Exists.

に記載される化合物(Cmpd)のいずれか1つから選択されるか、またはそれらの薬学的に許容され得る塩であり、重水素と指定されない任意の原子は、その天然の同位体存在度で存在する。 In one embodiment, the compound is a compound of formula I wherein Y ⁶ , Y ⁷ and Y ⁸ are each D, and the compound is Table 2 (below):

Any atom selected from any one of the compounds described in (Cmpd) or a pharmaceutically acceptable salt thereof and not designated as deuterium is in its natural isotopic abundance. Exists.

  In another set of embodiments, any atom not designated as deuterium in any of the above embodiments is present in its natural isotopic abundance.

またはその塩を作製するために有用であり、式中、重水素と指定されない任意の原子は、その天然の同位体存在度で存在する。 The following compounds are various compounds of the invention:

Or, useful for making salts thereof, any atom not designated as deuterium is present in its natural isotopic abundance.

  The synthesis of compounds of Formula I or Formula A can be readily accomplished by synthetic chemists having ordinary skill with reference to the exemplary syntheses and examples disclosed herein. Related procedures similar to those used for the preparation of compounds of formula I or formula A and intermediates thereof are disclosed, for example, in US Pat. No. 7,598,257 and Organic Letters, 2009, 11 (9): 1999-2009 Is done.

  Such methods utilize corresponding deuteration, optionally other isotope-containing reagents and / or intermediates, or areotope atoms in chemical structures to synthesize the compounds presented herein. It can be carried out inducing standard synthetic protocols known in the art for introduction.

Exemplary Synthesis Compounds of Formula I or Formula A are appropriately deuterated starting in a manner similar to the synthesis shown in US Pat. No. 7,598,257 and Organic Letters, 2009, 11 (9): 1999-2009. It can be prepared using materials.

  Compounds of formula I or formula A can also be prepared as shown in the following scheme.

Scheme 1. Preparation of compounds of formula I.

Scheme 1 discloses an exemplary preparation of compounds of formula I where Y ¹ , each Y ² and each Y ³ are deuterium, and Y ⁴ , each Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are hydrogen To do. Treatment of commercially available 4-chloro-7H-pyrrolo [2,3-d] pyrimidine 11 (Aldrich) with sodium hydride and SEM chloride in a manner similar to that described in WO 2010/083283 This is reacted with commercially available 13 to give 14. Instead of 11, 4-bromo-7H-pyrrolo [2,3-d] pyrimidine was used in the first step, and SEM-protected 4-bromo-7H-pyrrolo [2,3-d] pyrimidine (with 12 Similar) may be obtained, which can be reacted with 13 to give 14. 14 and 15 reactions prepared as disclosed in Scheme 2a below were performed in a manner similar to that described in Lin, Q. et al. Org. Lett. 2009, 11, 1999. 16 is obtained. The reaction is performed in the presence of chiral ligand 27 prepared as described in Lin, Q. et al. Treatment of NH ₄ OH and I ₂ converts 16 to 17. The 17 SEM protecting groups are then deprotected with LiBF ₄ and NH ₄ OH to give compounds of formula I.

Scheme 2a. Preparation of compound 15.

As shown in Scheme 2a, commercially available 18 is treated with phosphonium ylide 20 and DCl / D ₂ O to give 19, which is treated with 20 and DiBAl—H to give 15.

Scheme 2b. Preparation of compound 23.

Scheme 2c. Preparation of compound 26.

Compounds similar to 15 can also be prepared. For example, as shown in Scheme 2b, commercially available 21 can be converted to 23 in a manner similar to that disclosed in Scheme 2a. As another example, commercially available 24 can be converted to 26 in a manner similar to that disclosed in Scheme 2a and Scheme 2b, as shown in Scheme 2c. 23 is similar to that disclosed in Scheme 1, wherein Y ¹ and each Y ³ are deuterium, Y ⁴ , each Y ² , each Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are hydrogen. Can be converted to certain compounds of formula I. Similarly, 26 is in a manner similar to that disclosed in Scheme 1, wherein Y ¹ and each Y ² are deuterium, Y ⁴ , each Y ³ , each Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ Can be converted to a compound of formula I wherein is hydrogen.

The specific approaches and compounds described above are not intended to be limiting. The chemical structures in the schemes herein show variations defined in the present invention in balance with the definitions of chemical groups (parts, atoms, etc.) at corresponding positions in the compound formulas herein. Are identified by the same variable name (ie, R ¹ , R ² , R ^3, etc.). The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

  Additional methods of synthesis of compounds of Formula I or Formula A and their synthetic precursors, including those in pathways not explicitly shown in the schemes herein, are within the scope of chemists of ordinary skill in the art. Synthetic chemical transformations and group protection methodologies (protection and deprotection) useful for the synthesis of applicable compounds are known in the art, eg, Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al , Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed. , Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and their subsequent editions.

  The combinations of substituents and variants envisioned by this invention are only those that result in the formation of stable compounds.

Compositions The invention also provides an effective amount of a compound of Formula I or Formula A (including any of the formulas herein) or a pharmaceutically acceptable salt of said compound, as well as a pharmaceutically acceptable A non-pyrogenic pharmaceutical composition comprising the resulting carrier is provided. The carrier (s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, to the recipient in the amount used in the medicament. Not harmful to it.

  Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical composition of the present invention include, but are not limited to, ion exchangers, serum proteins such as alumina, aluminum stearate, lecithin, human serum albumin, phosphate Buffers such as salts, salts or electrolytes such as glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , Colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol And wool fat.

  If necessary, the solubility and bioavailability of the compounds of the invention in pharmaceutical compositions may be increased by methods well known in the art. One method includes the use of lipid excipients in the formulation. "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)", David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery" : Basic Principles and Biological Examples ", Kishor M. Wasan, ed. Wiley-Interscience, 2006.

Another known method of increasing bioavailability is optionally in the amorphous form of compounds of the invention formulated with poloxamers, such as LUTROL ^™ and PLURONIC ^™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. Is use. See U.S. Patent Nos. 7,014,866; and U.S. Patent Publication Nos. 20060094744 and 20060079502.

  The pharmaceutical composition of the present invention is suitable for oral, rectal, nasal, topical (for example, intraoral and sublingual), vaginal or parenteral (for example, subcutaneous, intramuscular, intravenous and intradermal) administration. Is mentioned. In certain embodiments, the compounds of the formulas herein are administered transdermally (eg, using transdermal patches or iontophoresis techniques). Other formulations may conveniently be provided in unit dosage forms such as tablets, sustained release capsules, and liposomes and may be prepared by any method well known in the pharmaceutical arts. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).

  Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid entities, or both, and then, if necessary, forming the product. Is done.

  In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration include capsules, sachets or tablets each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil liquid emulsions; It can be provided as a separate unit such as an oil-in-water liquid emulsion; liposome inclusion bodies; or pills. Soft gelatin capsules can be useful because they contain such suspensions that can advantageously increase the rate of absorption of the compound.

  In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. A lubricant such as magnesium stearate is also typically added. Diluents useful for oral administration in a capsule form include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

  Compositions suitable for oral administration include flavored ingredients, usually troches containing sucrose and acacia or tragacanth; and pastille tablets containing gelatin and glycerin or active ingredient in an inert base such as sucrose and acacia Is mentioned.

  Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may include antioxidants, buffers, bacteriostats and solutions that are isotonic with the blood of the intended recipient; Aqueous and non-aqueous sterile suspensions may be included that may contain suspending agents and bulking agents. The formulation can be provided in unit-dose containers or multi-dose containers, such as sealed ampoules and vials, and is frozen and dried immediately prior to use requiring only the addition of a sterile liquid carrier, such as water for injection. Stored (lyophilized). Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

  Such injection solutions may be in the form of, for example, a sterile injectable aqueous or oleagenous suspension. This suspension may be prepared according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among these, acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed such as synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene adducts. These oily suspensions or suspensions may also contain a long-chain alcohol diluent or dispersant.

  The pharmaceutical compositions of the invention can be administered in the form of suppositories for rectal administration. These compositions are prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the active ingredient. Can be prepared. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

  The pharmaceutical compositions of the invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other possible known in the art. It can be prepared as a solution in saline using a solubilizer or dispersant. See, for example, Rabinowitz JD and Zaffaroni AC, US Pat. No. 6,803,031, patented to Alexza Molecular Delivery Corporation.

  Topical administration of the pharmaceutical composition of the present invention is particularly suitable when the desired treatment involves areas or organs that are easily accessible by topical application. For topical administration limited to the skin, the pharmaceutical composition should be prepared with a suitable ointment containing the active component suspended or dissolved in a carrier. Single substances for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white gasoline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be prepared with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable simple substances include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of the present invention may also be applied topically to the lower small intestinal tract by an intestinal suppository formulation or in a suitable enema formulation. Topical transdermal patches and iontophoretic administration are also encompassed by the present invention.

  The application of the subject therapeutic agent can be local to be administered at the site of interest. Various techniques such as injection, use of catheters, troches, projectiles, pluronic gels, stents, sustained drug release polymers or other devices that provide internal access can be used to provide the target composition at the site of interest. .

  Thus, according to yet another aspect, the compounds of the invention can be integrated into a composition for coating an implantable medical device such as a prosthesis, an artificial valve, a tubular graft, a stent or a catheter. General preparations of suitable coatings and coated implantable devices are known in the art and are exemplified in US Pat. Nos. 6,099,562; 5,886,026 and 5,304,121. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating can optionally be further coated with a suitable top coat of fluorosilicone, polysaccharides, polyethylene glycols, phospholipids or mixtures thereof to impart controlled release properties of the composition. Coatings for invasive devices can be included in the definition of pharmaceutically acceptable carriers, adjuvants or vehicles when those terms are used herein.

  According to another aspect, the present invention provides a method for coating an implantable medical device comprising the step of coating with an above-described coating composition. It will be apparent to those skilled in the art that the coating of the device is performed prior to implantation into the mammal.

  According to another aspect, the present invention provides a method of impregnating an implantable drug release device comprising the step of contacting the implantable drug release device with a compound or composition of the present invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

  According to another aspect, the invention provides an implantable medical device coated with a compound of the invention or a composition comprising the compound, wherein the compound is therapeutically active.

  According to another aspect, the invention provides an implantable drug release device impregnated with or comprising a compound of the invention or a composition comprising the compound, wherein the compound is released from the device and is treated. Active.

  Where an organ or tissue is accessible for removal from a subject, such organ or tissue can be bathed in a medium containing the composition of the invention, or the composition of the invention can be It can be painted on or the composition of the invention can be applied in any other convenient way.

  In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or exhibit advantageous properties when administered with a compound having the same mechanism of action as ruxolitinib. Such agents include those shown to be useful in combination with ruxolitinib.

  Preferably, the second therapeutic agent is myelofibrosis such as primary myelofibrosis, polycythemia vera, post-erythrocytic myelofibrosis, chronic idiopathic myelofibrosis, essential post-thrombocytopenia myelofibrosis, etc. , And essential thrombocytopenia, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriasis and alopecia areata.

  In one embodiment, the second therapeutic agent is selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.

  In another embodiment, the present invention provides one or more separate dosage forms of a compound of the present invention and any of the second therapeutic agents described above, wherein the compound and the second therapeutic agent are related to each other. ing. The term “related to each other” as used herein refers to separate dosage forms encapsulated together or otherwise sold and administered together (less than 24 hours of each other). It means attached to each other so that it is readily apparent that it is intended to be continuous or simultaneously.

  In the pharmaceutical composition of the invention, the compound of the invention is present in an effective amount. As used herein, the term “effective amount” refers to an amount sufficient to treat the targeted disorder when administered on an appropriate dosing schedule.

  The dose correlation for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area can be approximately determined from the height and weight of the subject. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

  In one embodiment, an effective amount of a compound of the invention can range from 1 mg to 500 mg, such as from 5 mg to 100 mg, such as from 5 mg to 50 mg. Examples of ranges are 40 mg to 50 mg, 25 mg to 40 mg, 25 mg to 50 mg, 20 mg to 40 mg, 20 mg to 50 mg, 10 mg to 25 mg, 10 mg to 20 mg, 5 mg to 25 mg, 5 mg to 20 mg and 5 mg to 10 mg. In one embodiment, doses of 10 mg, 20 mg, 40 mg and 50 mg are administered once a day. In one embodiment, doses of 5 mg, 10 mg, 20 mg, 40 mg and 50 mg are administered twice daily.

  Effective doses are also as understood by those of skill in the art, the disease being treated, the severity of the disease, the route of administration, the sex of the subject, age and general health, excipient use, other treatments It depends on the concomitant treatment, eg the possibility of using other drugs and the judgment of the treating physician. For example, guidance for selection of an effective amount can be determined with reference to prescription information for ruxolitinib.

  For pharmaceutical compositions comprising a second therapeutic agent, an effective amount of the second therapeutic agent is usually about 20% to 100% of the dose utilized in a single therapy regimen using such agents. Preferably, the effective amount is about 70% to 100% of the normal monotherapy dose. Usual monotherapeutic doses for these second therapeutic agents are well known in the art. See, for example, Wells et al., Pharmacotherapy Handbook, 2nd edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, each incorporated herein by reference in its entirety. See Tarascon Publishing, Loma Linda, Calif. (2000).

  Some of the second therapeutic agents referred to above are expected to act synergistically with the compounds of the present invention. In this case, the effective amount of the second therapeutic agent and / or the compound of the invention may be reduced than is required in monotherapy. This can be achieved by minimizing the toxic side effects of each of the second therapeutic agents of the compounds of the present invention, synergistically improving efficacy, improving ease of administration or use, and / or overall compound preparation or formulation. It has the advantage of reduced costs.

Methods of treatmentIn another aspect, the invention provides a Janus-related kinase (JAK) in a cell comprising contacting the cell with one or more compounds of Formula I or Formula A, or a pharmaceutically acceptable salt thereof. Methods of inhibiting one or more of JAK1 and JAK2 are provided.

  According to another aspect, the present invention comprises administering to a subject in need of treatment of a disease beneficially treated with ruxolitinib an effective amount of a compound or composition of the present invention in the subject. Provides a method of treating a disease that is more beneficially treated. In one embodiment, the subject is a patient in need of such treatment. Such diseases are well known in the art and are disclosed, but not limited to, the following patent, US Pat. No. 7,598,257. Such diseases include, but are not limited to, diseases involving the immune system such as organ transplant rejection (eg, xenograft refection and graft-versus-host disease); multiple sclerosis, rheumatoid arthritis, juvenile arthritis , Autoimmune diseases such as type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorder; asthma, food allergy, atopic skin Allergic conditions such as inflammation and rhinitis; viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, varicella-zoster virus (VZV) and human papillomavirus (HPV); psoriasis ( Skin disorders such as psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g. contact dermatitis or allergic contact dermatitis) Cancers characterized by solid tumors (eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioma, Kaposi's sarcoma, Castleman Disease, melanoma), blood cancer (e.g., lymphoma, acute lymphoblastic leukemia or multiple myeloma), and cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (e.g., Cesar syndrome and fungus) Cancers including skin cancer such as sarcomas); polycythemia vera (PV), essential thrombocythemia (ET), myelogenous metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia ( CMML), myeloproliferative disorders (MPD) such as hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD); inflammatory diseases of the eye (eg, iritis, uveitis, scleritis, Conjunctivitis or related diseases), inflammatory diseases of the respiratory tract (e.g. rhinitis or sinusitis) And inflammatory diseases such as inflammatory myopathy such as myocarditis; systemic inflammatory response syndrome (SIRS) and septic shock Disease or condition associated with ischemic reperfusion injury or inflammatory ischemic events such as stroke or cardiac arrest; loss of appetite; cachexia; fatigue such as that caused by or associated with cancer; Sclerodermitis; fibrosis; hypoxia or astrogliosis such as diabetic retinopathy, conditions associated with cancer or neurodegeneration; ventilation; prostate, eg benign prostatic hypertrophy or benign prostatic hyperplasia Diseases such as an increase in the size of

  In one specific embodiment, the method of the invention is used in a subject in need of treatment for bone marrow fibers such as primary myelofibrosis, post-erythrocytic myelofibrosis, essential post-thrombocythemia myelofibrosis, etc. , Essential thrombocythemia or combinations thereof; pancreatic cancer; prostate cancer; breast cancer; leukemia, non-Hodgkin lymphoma; multiple myeloma; used to treat a disease or condition selected from psoriasis and combinations thereof The

  In another specific embodiment, the method of the invention is used in a subject in need of treatment for bone marrow such as primary myelofibrosis, post-erythrocytic myelofibrosis, and essential post-thrombocythemia myelofibrosis. Used to treat a disease or condition selected from fibrosis.

  Identifying a subject in need of such treatment can be made at the discretion of the subject or health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by testing or diagnostic methods). .

  In another embodiment, any of the methods of treatment described above comprise the additional step of co-administering one or more second therapeutic agents to a subject in need of treatment. The selection of the second therapeutic agent can be made from any second therapeutic agent known to be useful for co-administration with ruxolitinib. The choice of second therapeutic agent will also depend on the specific disease or condition being treated. Examples of second therapeutic agents that can be used in the methods of the present invention are those described above for combination compositions comprising a compound of the present invention and a second therapeutic agent.

  In particular, the combination therapy of the present invention comprises a compound of formula I or formula A and a second therapeutic agent in the following condition (a specific second therapeutic agent shown in parentheses after the description: myelofibrosis (lenalidomide) Or panobinostat); pancreatic cancer (capecitabine); and breast cancer (exemestane)) for co-administration to a subject in need of treatment.

  The term “co-administration” as used herein refers to a second dosage form as part of a single dosage form, such as a composition of the invention comprising a compound of the invention and a second therapeutic agent as described above. It means that the therapeutic agent can be administered together with the compounds of the invention or can be administered separately as multiple dosage forms. Alternatively, additional agents may be administered at the same time as or prior to administration of the compound of the invention. In such combination therapy treatment, the compound of this invention and the second therapeutic agent (s) are both administered by conventional methods. Administration of a composition of the invention comprising both a compound of the invention and a second therapeutic agent to a subject is the same therapeutic agent at any other time during the course of the treatment, any other second treatment Separate administration of the agent or any compound of the invention to the subject is not excluded.

  Effective amounts of these second therapeutic agents are well known to those skilled in the art, and administration guidance can be found in the patents and published patent applications referred to herein and edited by Wells et al., Pharmacotherapy Handbook 2nd edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical textbooks. However, it is within the skill of the art to determine an optimal effective dosage range for the second therapeutic agent.

  In one embodiment of the invention, when a second therapeutic agent is administered to a subject, the effective amount of the compound of the invention is less than its effective amount when no second therapeutic agent is administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount when the compound of the invention is not administered. In this case, undesirable side effects associated with high doses of either drug can be minimized. Other potential advantages (including but not limited to improved dosing schedules and / or reduced drug costs) will be apparent to those skilled in the art.

  In yet another aspect, the present invention relates to any one of Formula I or as a single composition or as separate dosage forms in the manufacture of a medicament for the treatment or prevention of the aforementioned diseases, disorders or syndromes in a subject. Provided is the use of a compound of formula A alone or in combination with one or more of the second therapeutic agents described above. Another aspect of the present invention is a compound of formula I or formula A for use in the treatment or prevention of a disease, disorder or syndrome described herein in a subject.

Examples Example 1. (R) -3- (4- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (2,2,5 , 5-d ₄ -Cyclopentyl) propanenitrile (Compound 107).
Scheme 3. Preparation of Compound 107

Step 1. Diethyl 2,2,5,5-d ₄ -cyclopentane-1,1-dicarboxylate (32). A solution of diethyl malonate (6.57 mL, 43.3 mmol) in ethanol (40 mL) was added to a solution of 21 wt% sodium ethoxide in ethanol (32.3 mL, 86.6 mmol), then 1,1,4,4-tetraduto (tetradeutero) -1,4-dibromobutane (31, 5.53 mL, 45.5 mmol, CDN isotope, 98 atomic% (atom%) D) was added. The resulting solution was stirred at reflux for 2 hours, then cooled to room temperature and diluted with excess water. The majority of ethanol was then removed by distillation and the resulting aqueous solution was extracted with ethyl acetate (3 × 75 mL). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 32 as a yellow oil that was carried forward without purification. . (9.45g, 100%).

Step 2. 2,2,5,5-d ₄ -Cyclopentane-1-carboxylic acid (33). To a solution (20 mL) of 32 (9.45 g, 43.3 mmol) in ethanol was added a solution of 5M sodium hydroxide (20 mL). Additional water (15 mL) was then added and the reaction was stirred at reflux for 3 hours. Upon cooling to room temperature, the reaction was diluted with excess water and most of the ethanol was removed by distillation. The aqueous solution was acidified with 1N HCl (pH <2) and then extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting bright orange solid was transferred to a pressure flask and water (140 mL) was added. The pressure flask was sealed and the reaction was stirred at 160 ° C. for 15 hours and then cooled to room temperature. The reaction was diluted with 1N HCl and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give an amber oil 33 (4.37 g, 86%), which was used without purification. did.

Step 3. 2,2,5,5-d ₄ -N-methoxy-N-methylcyclopentanecarboxamide (34). To a solution (60 mL) of 33 (4.37 g, 37.0 mmol) in acetonitrile was added N, O-dimethylhydroxylamine hydrochloride (4.33 g, 44.4 mmol), TBTU (12.5 g, 38.9 mmol) and N, N- Diisopropylethylamine (19.0 mL, 111 mmol) was added. The reaction was stirred at room temperature for 15 hours, then diluted with 1N HCl and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography (SiO _2, 0 to 50% ethyl acetate / hexane) to give 34 a clear oil (2.22 g, 37%). MS (ESI) 162.3 [(M + H) ⁺ ].

Step 4. 2,2,5,5-d ₄ -Cyclopentane-1-carboxaldehyde (35). To a solution (50 mL) of 34 (2.22 g, 13.8 mmol) in THF was added dropwise at 0 ° C. a solution of LiAlH ₄ in 1 M THF (24.8 mL, 24.8 mmol). The reaction was stirred at 0 ° C. for 1 h and then quenched by sequential dropwise addition of water (940 μL), 15% NaOH (940 μL) and water (2.82 mL). The quenched reaction was stirred at room temperature for 30 minutes, then filtered through Celite® and concentrated under reduced pressure. The resulting oil was diluted with 1N HCl and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 35 as a clear oil (850 mg, 60%), which was used without purification.

Step 5. 3- (2,2,5,5-d ₄ -cyclopentyl) acrylonitrile (36). To a 1M solution of potassium tert-butoxide in THF (8.74 mL, 8.74 mmol) was added dropwise at 0 ° C. a solution (12 mL) of diethylcyanomethyl phosphate (1.48 mL, 9.15 mmol) in THF. The reaction was warmed to room temperature, stirred for 15 minutes and cooled to 0 ° C. Aldehyde 35 (850 mg, 8.32 mmol) was then added dropwise as a solution in THF (3 mL). The reaction was stirred at room temperature for 48 hours, then diluted with excess water and extracted with diethyl ether (1 × 50 mL) and ethyl acetate (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 36 as a bright orange oil (1.17 g,> 100%), which was purified. Used without.

Step 6. (+/-)-(4- (1- (2-cyano-1- (2,2,5,5-d ₄ -cyclopentyl) ethyl) -1H-pyrazol-4-yl) -7H- Pyrrolo [2,3-d] pyrimidin-7-yl) methyl pivalate ((+/-) 38). To a solution (10 mL) of 37 (400 mg, 1.34 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002) in acetonitrile, 36 (418 mg, 3.34 mmol) Then, DBU (421 μL, 2.81 mmol) was added. The reaction was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with 1N HCl, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Normal phase column chromatography (SiO _2, 0 to 60% ethyl acetate / hexane) purification on, by reverse phase column chromatography (5% to 70% acetonitrile / water containing C18,0.1% formic acid), white foam The product (+/−) 38 was obtained (68 mg, 12%). 1H NMR (DMSO-d ₆ , 400 MHz) δ 8.84 (s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 7.74 (d, J = 3.8 Hz, 1H), 7.12 (d, J = 3.8 Hz, 1H), 6.24 (s, 2H), 4.54 (td, J = 9.7, 4.3 Hz, 1H), 3.30-3.15 (m, 2H), 2.39 (d, J = 9.8 Hz, 1H), 1.68 -1.36 (m, 4H), 1.08 (s, 9H); MS (ESI) 425.3 [(M + H) ⁺ ].

Step 7. (R)-(4- (1- (2-Cyano-1- (2,2,5,5-tetradetrocyclopentyl) ethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) methyl pivalate ((R) -38). Racemic compound (+/-) 38 (62 mg) is dissolved in acetonitrile at a concentration of 30 mg / mL and 500 μL of (+/-) 38 solution per injection using the isocratic method Were subjected to chiral separation by preparative HPLC on a Daicel ChiralPak AD column (20 × 250 mm, 10 μm): 30% isopropanol (+ 0.1% diethylamine) / 70% hexane (+ 0.1% diethylamine), flow rate 17 mL / Min. Under these conditions, baseline separation was reached, with (S) -38 eluting at 15.0 minutes and (R) -38 eluting at 20.2 minutes.

  Fractions containing the respective enantiomer were pooled and concentrated to give 28 mg of (S) -38 as a colorless film and 29 mg (R) -38 as a colorless film.

Step 8. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (2,2,5,5- Tetradeuterocyclopentyl) propanenitrile (Compound 107). Compound (R) -38 (28 mg, 0.066 mmol, 1 eq) was dissolved in methanol (1 mL) in a 20 mL scintillation vial. Sodium hydroxide (0.13 mL of 1M solution, 0.13 mmol, 2 eq) was added and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (10 mL) and brine (20 mL). The aqueous mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated. The crude material was purified using an Analogix automated chromatography system eluting with 0-6% methanol in dichloromethane. Product fractions were pooled and evaporated to give compound 107 as a white foam. Chiral purity> 99% ee (Chiralpak OD 4.6x250mm, 10um, 70% (hexane + 0.1% diethylamine) + 30% (isopropanol + 0.1% diethylamine), 1mL / min, 254nm retention time = 8.85min) Was found.

Example 2. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (3,3,4,4 Synthesis of -d ₄ -cyclopentyl) propanenitrile (Compound 103).
Scheme 4. Preparation of Compound 103

Step 1. Diethyl 3,3,4,4-d ₄ -cyclopentane-1,1-dicarboxylate (40). A solution of diethyl malonate (3.25 mL, 21.4 mmol) in ethanol (20 mL) was added to a solution of 21 wt% sodium ethoxide in ethanol (16.0 mL, 42.8 mmol), then 2,2,3,3-tetradose. Toro-1,4-dibromobutane (39, 4.95 g, 22.5 mmol, CDN isotope, 98 atom% D) was added. The resulting solution was stirred at reflux for 2 hours, then cooled to room temperature and diluted with excess water. The majority of ethanol was then removed by distillation and the resulting aqueous solution was extracted with ethyl acetate (3 × 75 mL). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a yellow oil, 40, which was then carried forward without purification. (4.67g, 100%).

Step 2. 3,3,4,4-d ₄ -Cyclopentane-1-carboxylic acid (41). To a solution of 40 (4.67 g, 21.4 mmol) in ethanol (10 mL) was added a solution of 5 M sodium hydroxide (10 mL). Additional water (10 mL) was then added and the reaction was stirred at reflux for 3 hours. Upon cooling to room temperature, the reaction was diluted with excess water and most of the ethanol was removed by distillation. The aqueous solution was acidified with 1N HCl (pH <2) and then extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting bright orange solid was transferred to a pressure flask and water (70 mL) was added. The pressure flask was sealed and the reaction was stirred at 160 ° C. for 15 hours and then cooled to room temperature. The reaction was diluted with 1N HCl and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give an amber oil 41 (1.93 g, 76%) that was used without purification. did.

Step 3. 3,3,4,4-d ₄ -N-methoxy-N-methylcyclopentanecarboxamide (42). To a solution (30 mL) of 41 (1.93 g, 16.3 mmol) in acetonitrile was added N, O-dimethylhydroxylamine hydrochloride (1.91 g, 19.6 mmol), TBTU (5.50 g, 17.1 mmol) and N, N- Diisopropylethylamine (8.52 mL, 48.9 mmol) was added. The reaction was stirred at room temperature for 15 hours, then diluted with 1N HCl and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography (SiO _2, 0 to 40% acetone / hexane) to give the 42 clear oil (1.47 g, 56%). MS (ESI) 162.3 [(M + H) ⁺ ].

Step 4. 3,3,4,4-d ₄ -Cyclopentane-1-carboxaldehyde (43). To a solution (35 mL) of 42 (1.47 g, 9.12 mmol) in THF was added a solution of 1M LiAlH ₄ in THF (16.4 mL, 16.4 mmol) at 0 ° C. The reaction was stirred at room temperature for 1 hour and then quenched at 0 ° C. by sequential dropwise addition of water (623 μL), 15% NaOH (623 μL) and water (1.87 mL). The quenched reaction was stirred at room temperature for 30 minutes, then filtered using Celite® and concentrated under reduced pressure. The resulting oil was diluted with 1N HCl and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 43 as a clear oil (767 mg, 82%), which was used without purification.

Step 5. 3- (3,3,4,4-d ₄ -cyclopentyl) acrylonitrile (44). To a solution (10 mL) of diethyl cyanomethyl phosphate (0.607 mL, 3.75 mmol) in THF was added dropwise at 0 ° C. a solution of 1M potassium tert-butoxide in THF (3.75 mL, 3.75 mmol). The reaction was stirred at 0 ° C. for 1 hour. Aldehyde 43 (767 mg, 7.51 mmol) was then added dropwise as a solution (3 mL) in THF. The reaction was stirred at room temperature for 15 hours, then diluted with excess 1: 1 water / brine and extracted with MTBE (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting oil was dissolved in CH ₂ Cl ₂ (100 ml) and washed with NaHSO ₃ (3 × 25 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 44 as a bright orange oil (537 mg, 57%), which was used without purification.

Step 6. (+/-)-(4- (1- (2-Cyano-1- (3,3,4,4-d ₄ -cyclopentyl) ethyl) -1H-pyrazol-4-yl) -7H- Pyrrolo [2,3-d] pyrimidin-7-yl) methyl pivalate ((+/-) 45). To a solution (15 mL) of 37 (514 mg, 1.72 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002) in acetonitrile, 44 (537 mg, 4.29 mmol) Then, DBU (540 μL, 3.61 mmol) was added. The reaction was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with 1N HCl, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Normal phase column chromatography (SiO _2, 0 to 60% ethyl acetate / hexanes) Purification on to give a white foam (+/-) 45 (368mg, 50 %). 1H NMR (DMSO-d ₆ , 400 MHz) δ 8.84 (s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.12 (d, J = 3.7 Hz, 1H), 6.24 (s, 2H), 4.53 (td, J = 9.7, 4.2 Hz, 1H), 3.32-3.14 (m, 2H), 2.41 (q, J = 8.7 Hz, 1H), 1.79 (dd, J = 12.6, 7.6 Hz, 1H), 1.36-1.11 (m, 3H), 1.08 (s, 9H) .; MS (ESI) 425.2 [(M + H) ⁺ ].

Step 7. (R)-(4- (1- (2-cyano-1- (3,3,4,4-d ₄ -cyclopentyl) ethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) methyl pivalate ((R) -45). Racemic compound (+/-) 45 (151 mg) was dissolved in acetonitrile at a concentration of 30 mg / mL and 1000 μL of (+/-) 45 solution per injection, using a homogeneous solvent method, with Daicel Subjected to chiral separation by preparative HPLC on a ChiralPak AD column (20 × 250 mm, 10 μm): 30% isopropanol (+ 0.1% diethylamine) / 70% hexane (+ 0.1% diethylamine), flow rate 17 mL / min. Baseline separation was reached under these conditions, with (S) -45 eluting at 15.5 minutes and (R) -45 eluting at 20.7 minutes.

  Fractions containing each enantiomer were pooled separately and concentrated to give 51 mg of colorless film (S) -45 and 53 mg of colorless film (R) -45.

Step 8. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (3,3,4,4- d ₄ -Cyclopentyl) propanenitrile (Compound 103). (R) -45 (53 mg, 0.13 mmol, 1 equivalent) was dissolved in methanol (2 mL) in a 20 mL scintillation vial. Sodium hydroxide (0.25 mL of 1M solution, 0.25 mmol, 2 eq) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 mL) and brine (20 mL). The aqueous mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified using an Analogix automated chromatography system eluting with 0-6% methanol in dichloromethane. The product fractions were pooled and evaporated to give about 103% pure white foam compound 103 with incompletely deprotected hydroxymethyl intermediate as the major impurity. It was unsuccessful to further improve the purity by further chromatography. 90% pure material was dissolved in THF (2 mL) and treated with a few drops of 10% aqueous sodium hydroxide solution at 40 ° C. for 8 hours to give complete conversion of compound 103. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a white foam. The foam was dissolved in a minimum amount of acetonitrile, diluted with water and lyophilized to give Compound 103 as a white solid (14 mg, 35% yield). Chiral purity> 99% ee (Chiralpak OD 4.6x250mm, 10um, 70% (hexane + 0.1% diethylamine) + 30% (isopropanol + 0.1% diethylamine), 1mL / min, 254nm retention time = 7.56min) Was found.

Example 3. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (cyclopentyl-d ₉ ) propanenitrile Synthesis Scheme of (Compound 127) 5. Preparation of Compound 127

Step 1. Diethyl 2,2,3,3,4,4,5,5-d ₈ -cyclopentane-1,1-dicarboxylate (47). A solution of diethyl malonate (6.24 mL, 41.1 mmol) in ethanol (40 mL), a solution of 21 wt% sodium ethoxide in ethanol (30.7 mL, 82.2 mmol), then 1,1,2,2,3,3 4,4-octadeutero-1,4-dibromobutane (46, 9.67 g, 43.2 mmol, CDN isotope, 98 atom% D) was added. The resulting solution was stirred at reflux for 2 hours, then cooled to room temperature and diluted with excess water. The majority of ethanol was then removed by distillation and the resulting aqueous solution was extracted with ethyl acetate (3 × 75 mL). Combine the organic layers, wash with brine, dry (Na ₂ SO ₄ ), filter and concentrate under reduced pressure to give 47 as a yellow oil (9.12 g, 100%), purify it. I carried it over to the next.

Step 2. Perdeutero cyclopentane-1-carboxylic acid (48). To a solution of 47 (9.12 g, 41.1 mmol) in ethanol (20 mL) was added 5 M sodium hydroxide solution (20 mL), followed by additional water (15 mL) and the reaction was refluxed for 3 h. Stir. Upon cooling to room temperature, the reaction was diluted with excess water and most of the ethanol was removed by distillation. The aqueous solution was acidified with 1N HCl (pH <2) and then extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting bright orange solid was transferred to a pressure flask and D ₂ O (120 mL) was added. The pressure flask was sealed and the reaction was stirred at 160 ° C. for 15 hours and then cooled to room temperature. The reaction was diluted with 1N HCl and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 48 as a yellow oil (4.58 g, 90%), which was used without purification.

Step 3. N-methoxy-N-methyl (cyclopentane-d ₉ ) carboxamide (49). To a solution (60 mL) of 48 (4.58 g, 37.2 mmol) in acetonitrile was added N, O-dimethylhydroxylamine hydrochloride (4.35 g, 44.6 mmol), TBTU (12.5 g, 39.1 mmol) and N, N- Diisopropylethylamine (19.4 mL, 112 mmol) was added. The reaction was stirred at room temperature for 15 hours, then diluted with 1N HCl and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting product was purified by column chromatography (SiO _2, 0 to 50% ethyl acetate / hexane) to give the 49 clear oil (3.41 g, 55%). MS (ESI) 167.2 [(M + H) ⁺ ].

Step 4. Perdetrocyclopentane-1-carboxaldehyde (50). To a solution (80 mL) of 49 (3.41 g, 20.5 mmol) in THF was added dropwise at 0 ° C. a solution of 1M LiAlH _{4 in} THF (37.0 mL, 37.0 mmol). The reaction was stirred at room temperature for 1 hour and then quenched at 0 ° C. by sequential dropwise addition of D ₂ O (1.41 mL), 15% NaOD / D ₂ O (1.41 mL) and D ₂ O (4.23 mL). The quenched reaction was stirred at room temperature for 30 minutes, then filtered through Celite® and concentrated under reduced pressure. The resulting oil was diluted with 1N DCl / D ₂ O and extracted with diethyl ether (3 × 50 mL). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 50 as a clear oil (1.79 g, 82%), which was used without purification.

Step 5. 3- (Perdetrocyclopentyl) acrylonitrile (51). To a solution (25 mL) of diethyl cyanomethyl phosphate (1.35 mL, 8.34 mmol) in THF was added dropwise at 0 ° C. a solution of 1M potassium tert-butoxide in THF (8.34 mL, 8.34 mmol). The reaction was stirred at 0 ° C. for 1 hour. Aldehyde 50 (1.79 g, 16.7 mmol) was then added dropwise as a solution in THF (5 mL). The reaction was stirred at room temperature for 15 hours, then diluted with excess 1: 1 water / brine and extracted with MTBE (3 × 50 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 51 as a bright orange oil (1.61 g, 74%), which was used without purification. did.

Step 6. (+/-)-(4- (1- (2-Cyano-1- (cyclopentyl-d ₉ ) ethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d] Pyrimidin-7-yl) methyl pivalate ((+/-) 52). To a solution (15 mL) of 37 (619 mg, 2.07 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002) in acetonitrile, 51 (673 mg, 5.17 mmol) Then DBU (650 μL, 4.35 mmol) was added. The reaction was stirred at room temperature for 15 hours and concentrated under reduced pressure. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with 1N HCl, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Normal phase column chromatography (SiO _2, 0 to 60% ethyl acetate / hexanes) Purification on to give a white foam (+/-) 52 (447mg, 50 %). 1H NMR (DMSO-d ₆ , 400 MHz) δ 8.84 (s, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.12 (d, J = 3.7 Hz, 1H), 6.24 (s, 2H), 4.53 (dd, J = 9.6, 4.2 Hz, 1H), 3.32-3.13 (m, 2H), 1.08 (s, 9H) .; MS (ESI) 430.3 [(M + H) ⁺ ].

Step 7. (R)-(4- (1- (2-cyano-1- (cyclopentyl-d ₉ ) ethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d] pyrimidine- 7-yl) methyl pivalate ((R) -52). Racemic compound (+/-) 52 (162 mg) was dissolved in acetonitrile at a concentration of 30 mg / mL and 1000 μL of (+/-) 52 solution per injection, using a homogeneous solvent method, with Daicel ChiralPak Subjected to chiral separation by preparative HPLC on an AD column (20 × 250 mm, 10 μm): 30% isopropanol (+ 0.1% diethylamine) / 70% hexane (+ 0.1% diethylamine), flow rate 17 mL / min. Under these conditions, baseline separation was reached, with (S) -52 eluting at 15.4 minutes and (R) -52 eluting at 20.5 minutes.

  Fractions containing each enantiomer were pooled separately and concentrated to give 61 mg of colorless film (S) -52 and 63 mg of colorless film (R) -52.

Step 8. (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (cyclopentyl-d ₉ ) propanenitrile ( Compound 127). (R) -52 (60 mg, 0.14 mmol, 1 equivalent) was dissolved in methanol (2 mL) in a 20 mL scintillation vial. Sodium hydroxide (0.28 mL of 1M solution, 0.28 mmol, 2 eq) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 mL) and brine (20 mL). The aqueous mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified using an Analogix automated chromatography system eluting with 0-6% methanol in dichloromethane. The product fractions were pooled and evaporated to give white foam compound 127 (34 mg) of about 90% purity with incompletely deprotected hydroxymethyl intermediate as the major impurity. It was unsuccessful to further improve the purity by further chromatography. 90% pure material was dissolved in THF (2 mL) and treated with a few drops of 10% aqueous sodium hydroxide solution at 40 ° C. for 8 hours to give complete conversion to compound 127. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a white foam. The foam was dissolved in a minimum amount of acetonitrile, diluted with water and lyophilized to give white solid compound 127 (19 mg, 42% yield). Chiral purity> 99% ee (Chiralpak OD 4.6x250mm, 10um, 70% (hexane + 0.1% diethylamine) + 30% (isopropanol + 0.1% diethylamine), 1mL / min, 254nm retention time = 7.55min) Was found.

Example 4. Evaluation of the metabolic stability of the compounds 103, 107 and 127 of the metabolic stability evaluation human CYP3A4 Supersomes in ^TM in CYP3A4 Supersomes ^TM
SUPERSOMES ^TM assay. A 10 mM stock solution of test compound, compounds 103, 107, 127 and ruxolitinib was prepared in DMSO. A 10 mM stock solution was diluted to 15.6 μM in acetonitrile (ACN). Human CYP3A4 supersomes ^™ (1000 pmol / mL, purchased from BD Gentest ^™ Products and Services) was diluted to 62.5 pmol / mL in 0.1 M potassium phosphate buffer, pH 7.4 containing 3 mM MgCl ₂ . Three diluted supersomes were added to wells of a 96-well polypropylene plate. A 10 μL aliquot of 15.6 μM test compound was added to the supersomes and the mixture was pre-warmed for 10 minutes. The reaction was started by adding pre-warmed NADPH solution. The final reaction volume was 0.5 mL and contained 50 pmol / mL CYP3A4 supersomes ^™ , 0.25 μM test compound, and 2 mM NADPH and 3 mM MgCl ₂ in 0.1 M potassium phosphate buffer, pH 7.4. The reaction mixture was incubated at 37 ° C. and 50 μL aliquots were removed at 0, 5, 10, 20 and 30 minutes and added to a 96 well plate containing 50 μL ice cold ACN with internal standard to stop the reaction. The plate was stored at 4 ° C. for 20 minutes, after which 100 mL of water was added to the wells of the plate, and the precipitated protein was then centrifuged until pelleted. The supernatant was transferred to another 96-well plate and analyzed for the amount of parental residue by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer.

Data analysis: The in vitro half-life (t _1/2 value) of the test compound was calculated from the relationship of the slope of the linear regression of LN (% parent residue) versus the incubation time:
In vitro t _1/2 = 0.693 / k, where k = − [slope of linear regression (ln) of% parent residue vs. incubation time].

The results of this experiment are shown in Table 3 and FIG. As shown in Table 3, the half-life of ruxolitinib was calculated to be 14.5 minutes. In contrast, each of compounds 103, 107, and 127 were more stable in supersomes, with half-lives calculated to be 16.9, 17.9, and 32.0 minutes, respectively. This represents a 17% increase in t _1/2 for compound 103, a 23% increase in t _1/2 for compound 107, and a 121% increase in t _1/2 for compound 127.

Example 5. Evaluation of metabolic stability in human liver microsomes Microsome assay: Human liver microsomes (20 mg / mL) are obtained from Xenotech, LLC (Lenexa, KS). β-nicotinamide adenine phosphate dinucleotide, reduced form (NADPH), magnesium chloride (MgCl ₂ ) and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

Determination of metabolic stability: A 7.5 mM stock solution of the test compound is prepared in DMSO. The 7.5 mM stock solution is diluted to 12.5-50 μM in acetonitrile (ACN). 20 mg / mL human liver microsomes are diluted to 0.625 mg / mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl ₂ . Add diluted microsomes to three wells of a 96-well deep well polypropylene plate. A 10 μL aliquot of 12.5-50 μM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. The reaction is started by adding a pre-warmed NADPH solution. The final reaction volume is 0.5 mL, containing 0.5 mg / mL human liver microsomes, 0.25-1.0 μM test compound, and 0.1 mM potassium phosphate buffer, pH 7.4, and ₂ mM NADPH in 3 mM MgCl ₂ . Incubate the reaction mixture at 37 ° C and remove 50 μL aliquots at 0, 5, 10, 20 and 30 minutes into shallow well 96-well plates containing 50 μL ice-cold ACN with internal standards to stop the reaction. Added. The plate is stored at 4 ° C. for 20 minutes, after which 100 μL of water is added to the well of the plate and centrifuged until the precipitated protein becomes a pellet. The supernatant is transferred to another 96-well plate and analyzed for the amount of parent residue by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer. Similar procedures are followed for the non-deuterated counterparts of compounds of Formula I or Formula A and the positive control 7-ethoxycoumarin (1 μM). The test is performed three times.

Data analysis: The in vitro t _1/2 of the test compound is calculated from the relationship of the slope of the linear regression (ln) of the% parent residue versus the incubation time.
In vitro t _1/2 = 0.693 / k
k =-[Slope of linear regression of% parent residue (ln) vs. incubation time]

  Data analysis is performed using Microsoft Excel software.

  Although not further described, it is believed that using the foregoing description and illustrative examples, those skilled in the art will be able to make and utilize the compounds of the present invention to perform the claimed methods. It should be understood that the foregoing description and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.

Claims (17)

Formula I:

Or a pharmaceutically acceptable salt thereof,
Y ¹ is hydrogen;
Each Y ² is independently selected from hydrogen and deuterium, provided that each Y ² bonded to a common carbon is the same;
Each Y ³ is independently selected from hydrogen and deuterium, provided that each Y ³ bonded to a common carbon is the same;
Y ⁴ is selected from hydrogen and deuterium;
Each Y ⁵ is the same and is selected from hydrogen and deuterium;
Each Y ⁶ , Y ⁷ and Y ⁸ is independently selected from hydrogen and deuterium;
However,
Each Y ² is deuterium, or each Y ³ is deuterium, or each Y ² and Y ³ is deuterium,
One of the following:
A position specifically designated “deuterium” is a compound or pharmaceutically acceptable salt thereof having at least 52.5% deuterium incorporation. The compound of claim 1, wherein each Y ² is hydrogen. The compound of claim 1, wherein each Y ³ is hydrogen. Each Y ⁵ is hydrogen, A compound according to any claims 1-3. The compound according to any one of claims 1 to 4, wherein each Y ⁷ and Y ⁸ is hydrogen. The compound according to any one of claims 1 to 5, wherein Y ⁶ is hydrogen. The compound according to any one of claims 1 to 6, wherein Y ⁴ is hydrogen. Each Y ⁶ , Y ⁷ and Y ⁸ is hydrogen and the compounds are represented in the following table:

Selected from any one of the compounds shown in (Cmpd),
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present in its natural isotopic abundance. Each Y ⁶ , Y ⁷ and Y ⁸ is D and the compounds are represented in the following table:

Selected from any one of the compounds shown in (Cmpd),
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present in its natural isotopic abundance. The compound is

2. A compound according to claim 1 or any of the pharmaceutically acceptable salts thereof selected from the group consisting of:   11. A compound according to any one of claims 1 to 7 or 10, wherein any atom not designated as deuterium is present in its natural isotopic abundance. 12. A compound according to any of claims 1 to 11, wherein the position specifically designated "deuterium" has at least 90% deuterium incorporation. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. 14. The composition of claim 13 , further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof. 14. The pharmaceutical composition of claim 13 , for treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriasis or a combination thereof. The pharmaceutical composition according to claim 15 , wherein the myelofibrosis is primary myelofibrosis, post-erythrocytic myelofibrosis, essential post-thrombocythemia myelofibrosis, essential thrombocythemia, or a combination thereof. . 14. A myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma comprising the composition of claim 13 and a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof A combination medicine for treating psoriasis or a combination thereof.

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