MX2013010067A - Derivatives of pyrazole-substituted amino-heteroaryl compounds. - Google Patents

Abstract

This invention relates to novel pyrazole-substituted amino-heteroaryl compounds of Fomula (I) and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of anaplastic lymphoma kinase (ALK).

Description

DERIVATIVES OF AMINO-HETEROARYL COMPOUNDS REPLACED WITH PIRAZOL BACKGROUND OF THE INVENTION Most current medicines suffer from poor absorption, distribution, metabolism, and excretion (ADME) properties that prevent their wider use or limit it with certain indications. The poor properties of ADME are also one of the main reasons for the failure of drug candidates in clinical trials. Although the technologies for formulation and strategies for drug production may be used in some cases to improve certain ADME properties, these methods may often fail to address the fundamental ADME problems that exist for most drugs. and drug candidates. One of these problems is the rapid metabolism caused by different drugs, which would otherwise be highly effective for the treatment of a disease, which are eliminated very quickly from the body. One possible solution to the rapid elimination of the drug is to increase the frequency or dose to maintain a sufficiently high drug level in the plasma. This, however, introduces different potential problems with treatment such as poor patient confidence with respect to Ref.:243573 dosage regimen, side effects that become more acute with higher doses, and increases the cost of treatment. A rapidly metabolized drug can also expose patients to toxic metabolites or undesirable reagents.

Another limitation of the ADME that affects many of the medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicity, or the safe dosage of these drugs may be limited such that patients receive a less than optimal amount of the active agent. In certain cases, modifying dosage ranges or formulation methods can help reduce adverse clinical effects, but frequently the formation of these undesirable metabolites is intrinsic to the metabolism of the compound.

In some cases, a metabolic inhibitor will be administered in addition to a drug that is eliminated very quickly. Such is the case with the class of protease inhibitor drugs that is used to treat HIV infection. The FDA recommends that these drugs be dosed in addition with ritonavir, an inhibitor of the cytochrome P450 3A4 enzyme (CYP3A4), the enzyme is typically responsible for its metabolism (see Kempf, DJ et al., Antimicrobial agents and chemotherapy, 1997, 41 ( 3): 654-60).

However, ritonavir causes adverse effects and adds to the pill burden for patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor of cinidine has been added to dextromethorphan in order to reduce the rapid metabolism of CYP2D6 of dextromethorphan in a treatment with pseudobulbar effect. Cynidine, however, has undesirable side effects that greatly limit its use in a potential combination therapy (see Ang, L. et al., Clinical Pharmacology and Therapeutics, 1994, 56 (6 Pt 1): 659-67. and the FDA labels cinidine at www.accessdata.fda.gov).

In general, the combination of drugs with cytochrome P450 inhibitors is not a satisfactory strategy to decrease the elimination of the drug. The inhibition of a CYP enzyme activity can affect the metabolism and the elimination of other drugs metabolized by the same enzyme. Inhibition of CYP can cause other drugs in the body to accumulate to toxic levels.

A potentially attractive strategy to improve one of the metabolic properties of the drug is modification with deuterium. In this method an attempt to slow down the metabolism mediated by the CYP of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a non-radioactive, stable, safe isotope of hydrogen. Compared with hydrogen, deuterium forms strong bonds with carbon. In selected cases, the increase in link strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety and / or tolerance. At the same time, due to the size and shape of deuterium are essentially identical to those of hydrogen, the replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug compared to the original chemical entity containing only hydrogen.

During the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported by a small percentage of approved drugs (see, eg, 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 Devel, 2006, 9: 101-09 ("Fischer")). The results have been variable and unpredictable. For some compounds with deuterium, a decrease in metabolic elimination was caused in vivo. For others, there was no change in metabolism. Still others showed a greater metabolic elimination. The variability in the effects of deuterium they have also left questions to the experts or have ruled out modification with deuterium as a viable design strategy in the drug to inhibit the adverse metabolism (see Foster on page 35 and Fisher on page 101).

The effects of deuterium modification on the metabolic properties of the drug are not predictable even when the deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a drug with deuterium can one determine if and how the rate of metabolism will change to that of its counterpart without deuterium. See, for example, Fukuto et al., (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site (s) where deuterium replacement is required and the degree of substitution with deuterium necessary to see an effect on the metabolism, if any, will be different for each drug.

Crizotinib also known as 3- [1 (R) - (2,6-dichloro-3-fluorophenyl) ethoxy] -5- [1- (4-piperidinyl) -lH-pyrazol-4-yl] pyridinyl -2- amine is known to inhibit the hepatocyte growth factor receptor kinase (c-met / HGFR) and also blocks tyrosine kinase from the anaplastic lymphoma kinase (ALK, for its acronym in English). A percentage of patients with cancer The large cell lung cells carry the kinase fusion gene of anaplastic lymphoma protein 4 associated with the kinotope of the quinoderm (EML4-ALK, for its acronym in English). EML4-ALK, when inserted into a normal cell, causes the cell to become cancerous. Crizotinib blocks the tyrosine kinase of the ALK domain of this fusion gene. See Sesaki, t et al., The Biology and Treatment of EML4-ALK Non-Small Cell Lung Cancer, Eur. J. Cancer, 2010, July; 46 (10): 1773-80.

Crizotinib is currently recommended for the approval of large cell lung cancer (NSCLC) and is undergoing Phase I / II clinical trials for solid and lymphoma cancer.

Treatment with crizotinib has been associated with events related to the gastrointestinal tract from medium to moderate and fatigue.

Despite the beneficial activities of crizotinib, there is a continuing need for new compounds to treat the diseases and conditions mentioned above.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to novel amino-heteroaryl compounds substituted with pyrazole and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of these compositions in methods for treatment of diseases and conditions that are beneficially treated by administering an anaplastic lymphoma kinase inhibitor (ALK) and the hepatocyte growth factor receptor kinase (c-met / HGFR).

Definitions The term "treatment" means decreasing, suppressing, attenuating, decreasing, stopping, or stabilizing the development or progression of a disease (eg, a disease or disorder delineated in the present description), lessens the severity of the disease or improves or lessens the severity of one or more symptoms associated with the disease.

"Disease" means any condition or disorder that harms or interferes with the normal function of a cell, your body or your organ.

It will be recognized that some variation of natural isotope abundance occurs in a synthesized compound depending on the origin of the chemical materials used in the synthesis. In this way, a crizotinib preparation will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, despite this variation, is small and immaterial compared to the degree of stable isotopic substitution of the compounds of this invention. See, for example, Wada, E. et al., Seikagaku, 1994, 66:15; Gannez, LZ et al. , Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

In the compounds of this invention any atom not specifically designed as a particular isotope means that it represents some stable isotope of this atom. Unless stated otherwise, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen in its naturally abundant isotopic composition. Unless stated otherwise, when a position is specifically designated as "D" or "deuterium", the position is understood to have deuterium in abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (that is, at least 45% deuterium incorporation).

The term "isotope enrichment factor" as used means the relationship between isotope abundance and the natural abundance of a specified isotope.

In other embodiments, a compound of this invention has an isotropic enrichment factor for each of the deuterium atoms designated at least 3500 (52.5% incorporation of deuterium in each of the designated deuterium atoms), at least 4000 ( 60% incorporation of deuterium), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least of 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 (99% incorporation of deuterium), or at least 6633.3 (99.5% incorporation of deuterium).

The term "isotopologist" refers to a species wherein the chemical structure differs from a specific compound of this invention only in its isotopic composition.

The term "compound", when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that it may be the isotopic variation between the constituent atoms of the molecules. Thus, it will be made clear to persons skilled in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain minor amounts of isotopologists having hydrogen atoms in one or more of the deuterium positions designated in this structure. The relative amount of these isotopologues in a compound of this invention will depend on various factors including the isotropic purity of deuterated reagents in the different steps of the synthesis used to prepare the compound. However, as discussed above, the relative amount of these inototo isotopologues will be less than 49.9% of the compound. In other modalities, the amount Relative of these isotopólogos in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1 %, or less than 0.5% of the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acidic group and a basic group of the compound, such as an amino functional group, or a basic and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, a salt of a compound provided is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable", as used herein, refers to a compound that is, within the scope of medical assessment, suitable for use in contact with the tissues of human and other mammals without undue toxicity, irritation, allergic response and the like and are adequate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is non-toxic when released from 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, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, acid tartaric, 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, para-bromophenylsulfonic acid, acid carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as inorganic and organic acids. These pharmaceutically acceptable salts of this form 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, butin-l, 4-diolate, hexin-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate , sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In a embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

Unless otherwise indicated, when a compound disclosed by a structure is named or shown without specifying the stereochemistry and having one or more chiral centers, it is meant to represent all possible stereoisomers of the compound.

The term "patient" as used herein includes a human or non-human animal, such as a mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey (e.g., macaque) from India), chimpanzee, or baboon. In one embodiment, the patient is a non-human animal. In another modality, the patient is human.

The compounds of the present invention (e.g., compounds of Formula I), may contain an asymmetric carbon atom, for example, as a result of substitution with deuterium or otherwise. As such, the compounds of this invention can exist either as individual enantiomers, or mixtures of two enantiomers. Accordingly, a compound of the present invention can exist as either a racemic mixture or a scaemic mixture, or as individual respecive stereoisomers that are substantially free of another possible stereoisomer. The term "substantially free other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and more preferably less than 2% of other stereoisomers are present. Methods of obtaining or synthesizing an individual stereoisomer for a given subject matter are known in the art and can be applied as practical for final compounds or for raw materials or intermediates.

Unless otherwise indicated, when a disclosed compound is named or displayed by a structure without specifying the stereochemistry and has one or more chiral centers, it is meant to represent all possible stereoisomers of the compound.

The term "stable compounds", as used herein, refers to compounds that possess sufficient stability to allow their production and that maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein ( eg, formulation in therapeutic products, intermediates that are used in the production of therapeutic compounds, which can be isolated, or intermediate compounds that can be stored, treating a disease or condition that responds to therapeutic agents).

"D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Ter" and "t-" each refers to tertiary. "US" refers to the United States of America.

"Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

Throughout this specification, a variable can generally refer to (eg, "each R") or can refer to specifically (eg, R1, R2, R3, etc.). Unless otherwise indicated, when a variable refers to generally, it means that it includes all the specific modalities of this particular variable.

DETAILED DESCRIPTION OF THE INVENTION Therapeutic Compounds The present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently selected from Cl, CH3 and CD3; R3 is CH3 or CD3; Xla, Xlb, Xa, X2, X3a, X3b, X4a, X4b, and X5 are each independently selected from hydrogen and deuterium; Y1 is hydrogen or deuterium; Y Y2 is hydrogen or deuterium; with the proviso that each of the R1 and R2 are Cl, each of the Xla, Xlb, X2a, X2b, X3a, X3b, Xa, X4b, and X5 is hydrogen and each of the Y1 and Y2 is hydrogen, then R3 is CD3.

In an embodiment of the compound of formula I, when R1 and R2 each is independently selected from Cl and CH3, each of Xla, Xlb, X2a, X2b, X3a, X3b, X4a, Xb, and X5 is hydrogen and each of Y1 and Y2 is hydrogen, then R3 is CD3 .

In one embodiment of a compound of formula I, Xla, Xlb are the same, X2a, X2b are the same, X3a, X3b are the same, and X4a, X4b are the same. In another aspect of this embodiment R1 and R2 are independently selected from Cl and CD3. In another aspect of this embodiment, R1 and R2 are the same and each is Cl. In yet another aspect of this embodiment, R1 and R2 are the same and each is CD3.

In one embodiment of a compound of formula I, Xla, Xlb, X2a and X2b are the same, X3a, X3b, X4a, Xb are the same and X5 is R1 and R2 are independently selected from Cl and CD3. In another aspect, each of Xla, Xlb, X2a and X2b are hydrogen; and each of the X3, X3b, X4a, X4b is deuterium. In one aspect, each of the Xla, Xlb, X2a and X2b are deuterium; and each of X3a, X3b, X4a, X4b is hydrogen. In one aspect, each of the Xla, Xlb, X2a, X2b, X3a, X3b, X4a and X4b is deuterium. In one aspect, each of Xla, Xlb, X2a, X2b, X3a, X3b, X4a and X4b is hydrogen. In one aspect of this mode, R1 and R2 are the same and each is Cl. In one aspect of this embodiment, R1 and R2 are the same and each is CD3.

In one embodiment of a compound of formula I, each of Xla, γ, X2a, X23, X3a, X3b, X43 and Xth is hydrogen, R1 and R2 are the same and are selected from CD3 and R3 is CH3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of X1, X3, X2a, X &, X3a, X3b, y is hydrogen, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CD3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is a¾.

In one embodiment of a compound of formula I, each of X13, X ^, X2a, X25, X3a, X3b, X43 and X413 is deuterium, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CH3 . In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of Xla, Xlb, X2a, X2b, X3a, X3b, X4a and X4b is deuterium, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CD3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of Xla, Xlb, Xa and X2b is deuterium, each of X3a, X3b, Xa and X4 is hydrogen, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CH3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of Xla, Xlb, X2a and X2 is deuterium, each of X3a, X3b, Xa and X4b is hydrogen, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CD3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of Xla, Xlb, X2a and X2b is hydrogen, each of X3a, X3b, X4a and X4 is deuterium, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CH3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, each of Xla, Xlb, X2a and Xb is hydrogen, each of X3a, X3b, X4a and Xb is deuterium, R1 and R2 are the same and are selected from Cl and CD3 and R3 is CD3. In one aspect, R1 and R2 each is Cl. In another aspect, R1 and R2 each is CD3.

In one embodiment of a compound of formula I, X5 is hydrogen, Y1 is hydrogen, Y2 is hydrogen and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, X2a and X2b, X3a, X3, X4a and X4b, is hydrogen. In one aspect each the same each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of the Xla, Xlb, X2a and X2b are hydrogen and each of the X3a, X3b, X43, X4 * 3 is deuterium. In one aspect each of Xla, X113, X2a and Xa3 is deuterium and each of X3a, X3b, X43, X * is hydrogen.

In one embodiment of a compound of formula I, X5 is hydrogen, Y1 is deuterium, Y2 is hydrogen and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of X13, ??, X2a and Xa, X3a, X313, X43 and X4, is hydrogen. In one aspect each of the same each of Xla, ^ ^, X23 and X20, X3a, X3b, X43 and X4 * 3, is deuterium. In one aspect each of Xla, Xlb, X2a and Xb are hydrogen and each of X3a, X3b, X4a, X4b is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, X3b, X4a, X4b is hydrogen.

In one embodiment of a compound of formula I, X5 is hydrogen, Y1 is hydrogen, Y2 is deuterium and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of X13, Xlb, X23 and X \ X33, X3b, X4a and X4b, is hydrogen. In one aspect each of them each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of X13, Xlb, X23 and X2b are hydrogen and each of X3a, X3b, X4a, X413 is deuterium. In one aspect each of the Xla, γ, X2a and X213 is deuterium and each of the X3a, X3b, X43, X413 is hydrogen.

In one embodiment of a compound of formula I, X5 is hydrogen, Y1 is deuterium, Y2 is deuterium and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, °, X2a and X2", X3a, X3b, X43 and X4b, is hydrogen. In one aspect each of them each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of Xla, Xlb, X2a and X2b are hydrogen and each of X3a, X3b, X4a, X4b is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, X3b, X4a, X4b is hydrogen.

In one embodiment of a compound of formula I, X5 is deuterium, Y1 is hydrogen, Y2 is hydrogen and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, Xa and X2b, X3a, X3b, X4a and X4b, is hydrogen. In one aspect each the same each of Xla, Xlb, X2a and X2b, X3a, X3, X4a and X4b, is deuterium. In one aspect each of Xla, Xlb, X2a and X2b are hydrogen and each of X3a, X3b, X4a, X4b is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, Xb, X4a, Xb is hydrogen.

In one embodiment of a compound of formula I, X5 is deuterium, Y1 is hydrogen, Y2 is hydrogen and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, X2a and X2b, X3a, X3b, Xa and X4b, is hydrogen. In one aspect each of them each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of Xla, Xl, X2a and X2b are hydrogen and each of X3a, X3b, X4a, X4b is deuterium. In one aspect each of the Xla, Xlb, X2a and x2b is deuterium and each of the X3a, X3b, X4a, X4b is hydrogen In one embodiment of a compound of formula I, X5 is deuterium, Y1 is deuterium, Y2 is hydrogen and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, X2a and X2 \ X3a, X3b, Xa and X4b, is hydrogen. In one aspect each of them each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of Xla, Xlb, X2a and X2b are hydrogen and each of X3a, X3b, Xa, Xb is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, X3b, X4a, X4b is hydrogen.

In one embodiment of a compound of formula I, X5 is deuterium, Y1 is hydrogen, Y2 is deuterium and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, X2 and X2b, X3a, X3b, X4a and X4b, is hydrogen. In one aspect each the same each of Xla, Xlb, X2a and Xb, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of Xla, Xlb, X2a and X2b are hydrogen and each of X3, X3b, Xa, X4b is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, X3b, X4a, X4b is hydrogen.

In one embodiment of a compound of formula I, X5 is deuterium, Y1 is deuterium, Y2 is deuterium and R1 and R2 are the same and are selected from Cl and CD3. In one aspect, each of Xla, Xlb, X2a and X2 \ X3a, X3b, Xa and X4b, is hydrogen. In a Each one of them, each of Xla, Xlb, X2a and X2b, X3a, X3b, X4a and X4b, is deuterium. In one aspect each of Xla, Xlb, X2a and X2b are hydrogen and each of X3a, X3b, Xa, X4b is deuterium. In one aspect each of Xla, Xlb, X2a and X2b is deuterium and each of X3a, X3b, X4a, Xb is hydrogen.

In an example of any of the foregoing embodiments, the compound is a compound of formula I as defined above wherein any atom not designed as deuterium is present in its natural isotopic abundance.

In one embodiment, the compound is selected from any of the compounds (Cmpd) set forth in Table 1 (following): Table 1. Compounds of Formula I (Continuation of Table 1. Compounds of Formula I) wherein any atom not designated as deuterium is present in its natural isotopic abundance, or a pharmaceutically acceptable salt thereof.

The synthesis of the compounds of Formula I can be easily accomplished by synthetic chemists with ordinary experience with reference to the Embodiment Synthesis and the Examples disclosed herein. Relevant procedures analogous to these are disclosed for use in the preparation of compounds of formula I and intermediates, for example, in Cui, J., O 2006/021881, Cui, J. WO 2006/021884, Lui, J. WO 2010/108103, O'Donnell, CJ; J. Med. Chem. 2010, 53, 1222-1237, and Shimizu, H. Tetrahedron. Lett. 2006, 47, 5927-5931.

These methods can be performed using the corresponding deuterated corresponding reagents and optionally, other reagents containing isotopes and / or intermediates to synthesize the compounds delineated herein, or invoking standard synthesis protocols known in the art to introduce isotopic atoms into a chemical structure .

Synthesis of Emplification Example A convenient method for synthesizing the compounds of formula I is shown in reaction scheme 1.

Scheme of reaction the: Synthetic Route of Compounds of Formula I (R1 and R2 = Cl) Reaction Scheme Ib: Synthetic Route of Compounds of Formula I (R1 and R2 = CD3) New chemical entities corresponding to formula I can be accessed by means of organic synthesis with multiple pass routinely practiced by persons with experience in the art and which is shown in reaction schemes Ia and Ib, above. First, the commercially available 2 ', 6'-dichloro-3' -f luoroacetophenone 10a can be attached to the hydrogen-deuterium exchange in the presence of deuterium chloride in deuterium oxide to provide entities where R3 = CD3.

Alternatively 10a can be attached to the Suzuki-Miyaura cross-coupling with trideuteromet-ilboronic acid (commercially available) to provide ketones 10b where R1 = R2 = CD3. After reduction of the carbonyl of the ketones 10a or 10b with boron hydride or boron deuteride the resulting racemic benzyl alcohol is acetylated with acetic anhydride. Enzyme resolution of the enantiomer mixture can be achieved with hepatic pig esterase (PLE) to provide chiral alcohols lia or 11b in greater 97.5% enantiomeric excess (ee).

Mitsunobu reversal of the secondary alcohol with 2-nitropyridin-3-ols (12 where Y1 = H or D) can be achieved with diisopropyl azidodicarboxylate (DIAD) and triphenylphosphine to provide biaryl ethers 13a or 13b. After the interconversions of two functional groups that involve the reduction of the nitro group and the introduction of iodine in the fifth position in the pyridine, the structure is ready for the union with the heterocycle 15.

The deuterated boron pinacolates can appropriately be attached with aryl iodides 13a or 13b by palladium catalyzed cross coupling under alkaline biphasic conditions. The removal of the tert-butyl carbamate protecting group (BOC) with concentrated hydrochloric acid produces the desired active pharmaceutical ingredient as the free base. Preparation of the salt (s) with appropriate pharmaceutical grade will be necessary and can be achieved using standard practices.

Reaction Scheme 2: Synthetic Route for Intermediate Compound 15 The preparation of piperidines with functional groups such as 16a, 16b, and the precursor in 16c and 16d, containing high levels of isotope abundance (Lui, J. WO 2010/108103) has been previously disclosed. Intermediate compounds 16c and 16d can be prepared from the ketone precursor through reduction with NaBD4 or NaB¾ respectively. 16a 16b Precursor for 16c and 16d 16d The conversion of the secondary alcohol into the corresponding mesylate allows the installation of the radical 3-iodo-H-pyrazole by means of direct low displacement. the anionic conditions. The elaboration of the iodine radical of 18 with the boron pinacolato is achieved, to give 15, by means of the reaction of dioxoboralane under palladium catalysts.

Reaction Scheme 3a: Synthetic Route of the Intermediate Compound 12b Reaction scheme 3b: Synthetic Route of the Compound Intermediary 12b The isotopólogos of 2-nitropyridin-3-ol such as 12b where Y1 = D can be prepared by regioselective bromination in 2-nitropyridin-3-ol 12a as reported by O'Donnell (J. Med. Chem. 2010, 53, 1222-1237). The metal halogen exchange followed by low temperature switching off with the appropriate isotope containing electrophiles after inserting the desired isotope in the correct position. Alternatively, direct exchange of hydrogen by deuterium under alkaline conditions and deuterium oxide will produce 12b directly from 12a.

The specific methods and compounds shown previously they do not try to be limiting. The chemical structures in the reaction schemes in the present show variables that are adequately defined with the definitions of the chemical group (radicals, atoms, etc.) of the corresponding position in the formulas of the compound herein, if it is identified with the same name of the variable (ie, R1, R2, R3, etc.) or not. The suitability of a chemical group in a structure of the compound that is used in the synthesis of another compound is within the knowledge of a person with ordinary skill in the art.

The additional methods of synthesis of compounds of formula I and their synthetic precursors, which include those within the routes not explicitly shown in the reaction schemes herein, are within the meaning of chemists with ordinary skill in the art. Synthetic chemical transformations and protective group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3rd Ed. 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 later editions of these.

The combinations of substituents and variables planned by this invention are only those that cause the formation of stable compounds.

Composition The invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula I (e.g., including any of the formulas herein), or a pharmaceutically acceptable salt of the compound; and an acceptable pharmaceutical carrier. The vehicle (s) are "acceptable" in the sense that it is compatible with the other ingredients of the formulation and, in the case of a vehicle, non-deleterious to the recipe thereof in an amount used in the medicament.

In some embodiments, the present invention provides a pyrogen-free pharmaceutical composition comprising an effective amount of a compound of Formula I (e.g., including any of the formulas herein), or a pharmaceutical salt of the compound or tautomer. and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carriers, adjuvants and carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as sulfate of protamine, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, block polymers of polyethylene-polyoxypropylene, polyethylene glycol and wool grease.

If required, the solubility and bioavailability of the compounds of the present invention in the pharmaceutical compositions can be improved by means of methods well known in the art. One method includes the use of lipid excipients in the formulation. See "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 Excipient in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Exemplars," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

Another known method for improving bioavailability is the use of an amorphous form of a compound of this invention is optionally formulated with a poloxamer, such such as LUTROL ™ and PLURONIC ™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States of America patent 7,014,866; and the publications of the United States of America Patent 20060094744 and 20060079502.

The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulas herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in the form of unit doses, e.g., tablets, extended-release capsules, and in liposomes, and may be prepared by any method well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).

These preparative methods include the step of bringing into association with the molecule with the administered ingredients such as the carrier constituting one or more secondary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or carriers. finely divided solids, or both and then, if necessary, fix the product.

In certain embodiments, the compound is administered orally. The compositions of the present invention for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of active ingredient; a powder or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatine capsules may be useful for containing these suspensions, which may beneficially increase the rate of absorption of the compound.

In the case of tablets for oral use, carriers that are commonly used are even used lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents 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 sweeteners and / or seasonings and / or colorants may be added.

Compositions suitable for oral administration include pills comprising the ingredients in a base seasoned, usually sucrose and acacia gum or tragacanth; and tablets comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

Compositions suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffering agents, bacteriostats and solutes that provide isotonicity to the formulation with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit dose or multiple dose containers, for example, sealed vials and flasks, and can be stored in a freeze-dried condition (lyophilized) that requires only the addition of the sterile liquid carrier, e.g., water for injections, immediately prior to its use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

The solutions for injection may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The injectable preparation Sterile can 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-butane diol. Among the acceptable carriers and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including the synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its triglyceride derivatives are useful in the preparation of injectables, such as natural pharmaceutically acceptable oils, such as olive oil, or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active components. These materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. These compositions are prepared according to techniques well known in the pharmaceutical formulating art and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other solubility or dispersing agents known in the art. See, e.g., Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition must be formulated with an appropriate ointment containing the active compounds suspended or dissolved in a vehicle. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a vehicle. The Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention can also be applied topically to the small intestinal tract by means of the rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

The application of the therapeutic compounds to the patient can be local, so that it is administered at the site of interest. Different techniques can be used to provide the compositions to the patient at the site of interest, such as injection, use of catheters, puncture needles, projectiles, pluronic gel, intravascular prostheses, extended-release polymers of the drug or other devices that provide access internal Thus, according to another embodiment, the compounds of this invention can be incorporated into compositions for coating a medical device that can be implanted, such as prostheses, artificial valves, vascular grafts, vascular prostheses, or catheters. Suitable coatings and general preparation of the coated implant devices are known in the art and are exemplified in US Patents 6,099,562; 5, 886.026; and 5,304,121. Coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally also be coated by a suitable final coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart the controlled release characteristics in the composition. Coatings for invasive devices will be included within the definition of the pharmaceutically acceptable carrier, adjuvant or vehicle, as these terms are used herein.

According to another embodiment, the invention provides a method for coating an implantable medical device comprising the step of contacting the device with the coating composition described above. It will be obvious to persons skilled in the art that the coating of the device is presented prior to implantation within the mammal.

According to another embodiment, the invention provides a method for impregnating a device that can be implanted for the release of the drug comprising the step of contacting the delivery device of the drug. drug with a compound or composition of this invention. Devices that can be implanted for drug delivery include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafer-shaped pellets.

According to another embodiment, the invention provides a medical device that can be implanted coated with a compound or a composition comprising a compound of this invention, such that the compound is therapeutically active.

According to another embodiment, the invention provides a device for delivery of the implantable drug impregnated with or containing a compound or a composition comprising a compound of this invention, such that the compound is released from the device and is therapeutically active.

When an organ or tissue is accessible due to the removal of the patient, this organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted within the organ, or a composition of this invention may be applied. in any other convenient way.

In another embodiment, a composition of this invention further comprises a second therapeutic agent or a combination of the second therapeutic agent. The second therapeutic agent (s) can be selected from any known therapeutic compound or agent that has or demonstrates advantageous properties when administered with a compound having the same mechanism of action as crizotinib. These agents include those indicated as being useful in combination with crizotinib, including but not limited to those described in US2011003805, and CN101836991.

Preferably, the second therapeutic agent (s) is an agent useful in the treatment or prevention of a cancer, more specifically prostate cancer, osteosarcoma, lung cancer, particularly large cell lung cancer, breast cancer, endometrial cancer, glioblastoma, colorectal cancer, ovarian cancer, pancreatic cancer, kidney cancer, small bowel cancer, esophageal cancer or gastric cancer.

In one embodiment, the second therapeutic agent is selected from kinase inhibitors. In one aspect of this embodiment, the kinase inhibitor is selected from erlotinib, sorafenib, a deuterated form of erlotinib as disclosed in U.S. Patent Application No. 11 / 957,442 and in U.S. Patent Application No. 12 / 413,510, a deuterated form of sorafenib as disclosed in PCT Patent Application No. PCT / US2009 / 053595), PF-00299804 and N-. { 2 - [4 - ( { 3 -chloro-4 - [3- (trifluoromethyl) phenoxy] phenyljamino) -5H-pyrrolo [3,2-d] irimidin-5-yl] ethyl} -3-hydroxy-3-methylbutanamide (See US Patent Publication 2011/0003805). In a more specific modality, the deuterated form of erlotinib is the compound TO, In another more specific modality, the deuterated form erlotinib is compound B, (B) In a more specific modality the deuterated form of sorafenib is compound C, (C) In another aspect the inhibitor is erlotinib or sorafenib. In a aspect the kinase inhibitor is a deuterated form of erlotinib (as disclosed in the patent applications referred to above) or a deuterated form of sorafenib (as disclosed in the patent applications referred to above).

In one embodiment, a composition of this invention comprises a combination of a compound of formula I with two therapeutic agents selected from kinase inhibitors. In one aspect of this embodiment the combination is with erlotinib or a deuterated form of erlotinib as disclosed in US Patent Application No. 11/957, 442 and in the US patent application No. 12/413, 510, and sorafenib or a deuterated form of sorafenib as disclosed in US Patent Application No. PCT / US2009 / 053595). In a more specific aspect of this modality the combination is with erlotinab or compound A, and sorafenib or compound C. In another more specific aspect of this modality, the combination is with erib inib or compound B, and sorafenib or compound C. In one aspect of this modality the combination is erlotinib and sorafenib. In one aspect of this modality the combination is a deuterated form of erlotinib and a deuterated form of sorafenib. In one aspect of this modality the combination is a deuterated form of erlotinib and sorafenib. In one aspect of this modality the combination of erlotinib and a deuterated form of sorafenib.

In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the second therapeutic agents described. above, wherein the compound and the second therapeutic agent are associated with one another. The term "associated with another" used herein means that the separate dosage forms are packaged together or otherwise bound to another such that it is apparent that the separate dosage forms are planned to be sold and administered together (within less than 24 hours one from the other, consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount that, when administered in an appropriate dosage regimen, is sufficient to treat the target condition.

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

In one embodiment, an effective amount of a compound of this invention can have ranges from 25 mg to 500 mg per treatment. The treatment is typically administered once or twice a day. In more specific embodiments, the effective amount may be one of the following quantities or ranges: 30 mg, preferably administered orally twice a day; 250 mg, preferably administered orally twice a day; 200 mg, preferably administered orally twice a day, or once a day; 100 mg, preferably administered orally once a day; 50 mg, preferably administered orally once a day; 200 to 300 mg, preferably administered orally twice a day; or of 50-200 mg, preferably administered orally once a day.

Effective doses will also vary, as recognized by persons with experience in the art, depending on the diseases treated, the severity of the disease, the route of administration, sex, age and the general condition of the patient's health, use of the excipient, the possibility of complementary use with other therapeutic treatments such as the use of other agents and the assessment of the attending physician. For example, the guide for selecting the effective dose can be determined with reference to the prescription information for crizotinib.

For pharmaceutical compositions comprising a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dose normally used in a monotherapy regimen using only this agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic doses of these second therapeutic agents are well known in the art. See, e.g., Wells et al., Eds. , Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of these references are incorporated herein by reference in its entirety.

It is expected that some of the second therapeutic agents referred to above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and / or the compound of this invention which will be reduced as required in monotherapy. This has the advantage of minimizing the toxic side effects of either the second therapeutic agent of a compound of this invention, improving synergy in efficacy, improving the ease of administration or use and / or reducing the total expense of the preparation or formulation of the drug. compound.

Treatment Methods In another embodiment, the invention provides a method for modulating the activity of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor kinase (c-met / HGFR) in a cell, which comprises contacting a cell with one or more compounds of formula I herein, or a pharmaceutically acceptable salt thereof.

According to another embodiment, the invention provides a method for treating a disease that is beneficially treated by inhibiting ALK and c-met / HGFR, eg, crizotinib, in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound or a composition of this invention. In one modality the subject is a patient in need of this treatment. These diseases are well known in the art and are disclosed in, but are not limited to the following patents and publication applications: WO 2006/021884. These diseases include, but are not limited to, cancer, in particular, lung cancer, large cell lung cancer, bone cancer, pancreatic cancer, skin cancer, neck and head cancer, cutaneous or intraocular melanoma, uterine cancer, cancer ovarian cancer, rectal cancer, anal cancer, stomach cancer, colorectal cancer, colon cancer, gastric cancer, breast cancer, endometrial cancer, fallopian tube carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphoma, soft tissue sarcoma, bladder cancer, kidney or urethral cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS, for short) in English), primary CNS lymphoma, axial spinal tumors, glioblastomas, brainstem glioma, neuroblastoma, pituitary adenoma, solid tumors or a combination of one or more previous cancers. These diseases also include abnormal cell growth disorders wherein the disease is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hyperplasia, and retinitis.

According to another embodiment, the invention provides a method of treating abnormal cell growth in a mammal.

In a particular embodiment, the method of this invention is used to treat a disease or condition selected from lymphoma, neuroblastoma, solid tumors and large cell lung cancer in a subject in need thereof.

Identifying a subject in need of this treatment may be the assessment of a patient or a health care professional and may be subjective (eg, opinion) or objective (eg, measurable by a test or method). of diagnosis).

In another embodiment, any of the above methods of treatment comprises further steps of complementary administration to the patient in need of these with one or more of the second therapeutic agents. The choice of the second therapeutic agent can be made from any second therapeutic agent that is known to be useful for the complementary administration with crizotinib. The choice of the second therapeutic agent also depends on the particular disease or condition to be treated. Examples of the second therapeutic agent that can be employed in the methods of this invention are those set forth above for use in combination with the compositions comprising a compound of this invention and a second therapeutic agent.

In particular, the combination of therapies of this invention includes the complementary administration of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent to a patient in need of this treatment of the following conditions (with the second agent particular therapeutic indicated in parentheses following the indication: lung cancer of large cells PF-00299804).

The term "complementary administration" as used herein means that the second therapeutic agent can be administered together with a compound of this invention comprising a compound of the invention and a second therapeutic agent as described above) or as multiple dosage forms. separated. Alternatively, the additional agent may be administered prior to, consecutively with, or after administration of a compound of this invention. In this combination therapy treatment, both compounds of this invention and the second therapeutic agent (s) are administered by conventional methods. The administration of a composition of this invention, which comprises both a compound of the invention and a second therapeutic agent, to a patient does not preclude the separate administration of the same therapeutic agent, any other second therapeutic agent or any compound of this invention to the patient in another time during the course of the treatment.

Effective amounts of these second therapeutic agents are well known to those skilled in the art and guide the dosage that may be found in published patents and patent applications referred to herein, as well as in Wells et al., Eds. , Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeiam Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the scope of the skilled person to determine the range of the effective optimal amount of the second therapeutic agent.

In one embodiment of the invention, where a second therapeutic agent is administered to a patient, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount which would be where the compound of this invention is not administered. In this way, unwanted side effects with high doses of any agent can be minimized. Other potential advantages (including, without limitation, improved dosage regimens and / or the reduced cost of the drug) will be apparent to those skilled in the art.

In yet another aspect, the invention provides the use of a compound of formula I alone or together with one or more of the therapeutic agents described above in the production of a medicament, either as a single composition or as separate dosage forms, for the treatment or prevention in a patient of a disease, disorders or symptoms discussed above. Another aspect of the invention is a compound of formula I, or a pharmaceutically acceptable salt, for use in the treatment or prevention in a patient with a disease, disorder or symptom thereof delineated herein.

Example. Metabolic Stability Assessment Test Mierosoma1 ·. n liver microsomes (20 mg / mL) were obtained from Xenotech, LLC (Lenexa, KS). The reduced form of (NAHPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich ß-nicotinamide adenine dinucleotide phosphate.

Determination of Metabolic Stability: 7.5 mM of the storage solutions of the test compounds were prepared in DMSO. The 7.5 mM storage solutions were diluted to 12.5-50 μ? in acetonitrile (ACN). n liver microsomes 20 mg / mL were diluted to 0.625 mg / mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl2. The diluted microsomes are added to the wells of a polypropylene plate with 96 deep wells in triplicate. An aliquot of 10 of the test compound 12.5-50 μ? to the microsomes and the mixture was preheated for 10 minutes. The reactions were initiated with the addition of the previously heated NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg / mL of liver microsomes of n, the test compound 0.25-1.0 μ ?, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl2. The reaction mixtures were incubated at 37 ° C and aliquots of 50] iL were extracted at 0, 5, 10, 20 and 30 minutes and added to shallow 96-well plates containing 50 μ? of ACN cooled with ice with internal standard to stop the reactions. The plates were stored at 4 ° C for 20 minutes after which 100 μl of water was added to the wells of the plate before centrifugation to granulate the precipitated proteins. The supernatants were transferred to another 96-well plate and their amounts of the remnants of origin were analyzed by LC-MS / MS using an Applied Bio-Systems API 4000 mass spectrometer. The same procedure was followed for the non-deuterated counterpart of the compound of formula I and the positive control, 7-ethoxycoumarin (1 μ?). The test was done in triplicate.

Data Analysis: The in vitro t½ was calculated for the test compounds from the slopes of the linear regression of the ratio of% of the remnant of origin (ln) vs the incubation time, in vitro t½ = 0.693 / k k = - [slope of the linear regression of the% of the remnant of origin (ln) vs the incubation time] The analysis of the data was done using Microsoft Excel Software Without further description, it is believed that persons of ordinary skill in the art can, using the foregoing description and illustrative examples, make and use the compounds of the present invention and practice the claimed methods. It should be understood that the above discussion and examples simply present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that different modifications and equivalences may be made without departing from the perspective and scope of the invention.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. Compound of formula I: or a pharmaceutically acceptable salt thereof, characterized in that: R1 and R2 are each independently selected from Cl, CH3 and CD3; R3 is CH3 or CD3; Xla, Xlb, X2a, X2b, X3a, X3b, X4a, X4b, and X5 are each independently selected from hydrogen and deuterium; Y1 is hydrogen or deuterium; Y Y2 is hydrogen or deuterium; with the proviso that each of the R1 and R2 are Cl, each of the Xla, Xlb, Xa, X2b, X3a, X3b, Xa, X4b, and X5 is hydrogen and each of the Y1 and Y2 is hydrogen, then R3 is CD3.

2. Compound according to claim 1, characterized in that Xla, Xlb are the same, Xa, X2b are the same, X3a, X3b are the same, and X4a, X4b are the same; and R1 and R2 are independently selected from Cl and CD3.

3. Compound according to claim 2, characterized in that Xla, Xlb, X2a and X2b are the same, X3a, X3b, X4a, X4b, are the same.

4. Compound according to claim 3, characterized in that R1 and R2 are the same.

5. Compound according to claim 4, characterized in that each X1, each X2, each X3 and each X4 is hydrogen.

6. Compound according to claim 4, characterized in that each X1, each X2, each X3 and each X4 is deuterium.

7. Compound according to claim 4, characterized in that each X1 and each X2 are hydrogen; and every X3 and each X4 are deuterium.

8. Compound according to claim 4, characterized in that each X1 and each X2 are deuterium; and each X3 and each X4 are hydrogen.

9. Compound according to any of claims 5-8, characterized in that X5 is hydrogen, Y1 is hydrogen and Y2 is hydrogen.

10. Compound according to any of claims 5-8, characterized in that X5 is hydrogen, Y1 is deuterium and Y2 is hydrogen.

11. Compound according to any of claims 5-8, characterized in that X5 is hydrogen, Y1 is hydrogen and Y2 is deuterium.

12. Compound according to any of claims 5-8, characterized in that Xs is hydrogen, Y1 is deuterium and Y2 is deuterium.

13. Compound according to any of claims 5-8, characterized in that X5 is deuterium, Y1 is hydrogen and Y2 is hydrogen.

14. Compound according to claims 5-8, characterized in that X5 is deuterium, Y1 is deuterium and Y2 is hydrogen.

15. Compound according to any of claims 5-8, characterized in that X5 is deuterium, Y1 is hydrogen and Y2 is deuterium.

16. Compound according to any of claims 5-8, characterized in that X5 is deuterium, Y1 is deuterium and Y2 is deuterium.

17. Compound according to claim 3 or 4, characterized in that R3 is CH3.

18. Compound according to claim 3 or 4, characterized in that R3 is CD3.

19. Compound according to claim 4, characterized in that it is selected from any of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

20. Compound according to any of claims 1-19, characterized in that any atom not designated as deuterium is present in its natural isotopic abundance.

21. A pyrogen-free pharmaceutical composition characterized in that it comprises a compound according to claim 1 or 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. Composition according to claim 21, characterized in that it also comprises a second therapeutic agent selected from kinase inhibitors.

23. Composition according to claim 22, characterized in that the kinase inhibitor is selected from erlotinib, d-erlotinib, sorafenib, d-sorafenib, PF-00299804 and 454283.

24. Composition according to claim 21, characterized in that it also comprises a combination of two second therapeutic agents selected from erlotinib or d-erlotinib and sorafenib or d-sorafenib.

25. Method for treating a disease or condition selected from cancer, in particular, lung cancer, large cell lung cancer, bone cancer, pancreatic cancer, skin cancer, neck and head cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer , rectal cancer, cancer of the anal region, stomach cancer, colorectal cancer, colon cancer, gastric cancer, breast cancer, endometrial cancer, fallopian tube carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, prostate cancer, leukemia chronic or acute, lymphoma, soft tissue sarcoma, bladder cancer, kidney or urethral cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, axial spinal tumors, glioblastomas, brainstem glioma, neuroblastoma, pituitary adenoma, solid tumors or a combination of one or more previous cancers; disease benign proliferative, which includes, but is not limited to, psoriasis, benign prosthetic hyperplasia and retinosis in a subject, characterized in that it comprises the step of administering to the subject in need thereof a composition in accordance with claim 21.

26. Method according to claim 25, characterized in that the disease or condition is selected from large cell lung cancer (NSCLC), solid tumor cancer, neuroblastoma and lymphoma.

27. Method according to claim 26, characterized in that the disease or condition is large cell lung cancer (NSCLC).